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Signal Transducers and Activators of Transcription: Novel Targets for Anticancer Therapeutics

¡¡¡¡Tammy Bowman, PhD; Hua Yu, PhD; Sa?d Sebti, PhD; William Dalton, PhD, MD; and Richard Jove, PhD

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The disruption of STAT signaling blocks neoplastic transformation, thus
making inhibitors of STAT proteins a potential novel molecular approach to treat human cancer.

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Background: Through specific activation of gene expression, the family of proteins known as signal transducers and activators of transcription (STATs) converts extracellular stimuli into diverse biological responses. Beyond the normal signaling functions of STATs, recent evidence indicates that aberrant activation of STATs contributes to neoplastic transformation.
Methods: Current literature pertaining to the role of STAT proteins in oncogenesis is presented. Also, the rationale for developing novel approaches to disrupt STAT signaling is discussed, and the potential of STATs as anticancer targets in treating human cancer is reviewed.
Results: The discovery that certain oncoproteins constitutively activate specific STATs, coupled with observations that elevated STAT activity occurs frequently in a spectrum of human tumors, establishes a direct link between STAT activation and neoplastic transformation. Significantly, abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo systems. These results make STATs attractive targets for rational design of small molecule inhibitors and gene therapy approaches to disrupt STAT signaling.
Conclusions: As a result of genetic, biochemical, and crystallographic analyses, the functional domains of STAT proteins have been well characterized. Based on these data, selective inhibitors of STAT function can be designed. Because disrupting STAT signaling has proven effective in blocking neoplastic transformation, it is proposed that STAT proteins represent promising targets for development of novel molecular therapeutics to treat human cancer.
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Introduction

Signal transduction (by growth factors, for example) is classically thought to employ a series of second messengers or intermediaries that act sequentially to relay extracellular stimuli to the nucleus. In contrast, studies of interferon (IFN)-dependent gene expression have led to the discovery of novel pathways that signal directly from the cell surface to the nucleus.1 Essential mediators of signaling in these direct pathways are the signal transducers and activators of transcription (STATs). STAT proteins comprise a family of transcription factors that become activated by tyrosine kinases in the cytoplasm and then migrate to the nucleus where they directly regulate gene expression.2 Thus, STATs perform a dual function with respect to signal transduction and gene regulation, thereby obviating the need for additional intermediaries.

Structure-Function Relationships in STAT Proteins

Seven mammalian STAT family members (Stat1 through Stat6, with Stat5a and Stat5b representing distinct genes) have been molecularly cloned and share common structural elements.3 Fig 1 is a generalized diagram depicting the location of important structural motifs common to most STAT family members. These domains and their associated functions have been elucidated based on biochemical and molecular studies. Each STAT molecule contains an Src-homology 2 (SH2) domain, a common protein-protein interaction domain among signaling proteins.4 Monomeric, inactive STAT proteins associate with each other to form active dimers through a key phosphotyrosine (pY) residue, which binds to the SH2 domain of another STAT monomer. Furthermore, such reciprocal SH2-pY interactions are critical for STAT functions, including nuclear transport and DNA binding. Thus, the activating event in STAT signaling is tyrosine phosphorylation. The DNA-binding domain resides in the N-terminal portion of the STAT molecule.5 Located within the C-terminal portion is the transactivation domain, which contains a serine residue, the phosphorylation of which is required for maximal transcriptional activity.6 Due to the structure-function relationships inherent in STAT activation, these structural domains pose excellent targets for the design and development of small molecule inhibitors that disrupt STAT signaling.

Fig 1. ¡ª Generic structure of a STAT protein illustrating common functional domain elements shared by STAT family members. The sites of tyrosine (Y) and serine (S) phosphorylation are shown. SH2 = Src-homology 2 domain, N = amino terminus, C = carboxyl terminus.

Role of STATs in Normal Signal Transduction

The following sequence of events illustrates the prevailing model of the role of STATs in normal signaling (Fig 2).3,7,8 This signal cascade initiates when cytokines (such as IFNs and members of the interleukin [IL] family) or growth factors (epidermal growth factor and platelet-derived growth factor, for example) bind to their cognate cell surface receptors. Growth factor receptors possess intrinsic tyrosine kinase activity and phosphorylate STATs directly, thereby activating STAT signaling. In contrast, cytokine receptors lack intrinsic kinase activity and must recruit members of the Janus kinase (JAK) family of cytoplasmic tyrosine kinases to activate STATs. Depending on which STAT family members are activated, STATs may associate as homodimers or heterodimers9 and then translocate to the nucleus. The activated STAT dimers then bind to specific DNA-response elements in promoters10 and induce expression of target genes.

Fig 2. ¡ª Signal transduction pathways leading to STAT activation. Stimulation with growth factors or cytokines at the cell surface results in receptor activation and subsequent tyrosine phosphorylation of STATs. Phosphorylation of STATs induces dimerization and translocation to the nucleus, where STAT dimers bind to specific STAT response elements and directly regulate gene expression. In contrast to normal signaling, oncogenic PTKs constitutively activate STATs, leading to deregulated expression of STAT-dependent genes. In some cases, but not all, JAK family tyrosine kinases are known to have a role in STAT activation.

In order for cells to respond to their microenvironments, extracellular stimuli must be received and transmitted to the nucleus such that specific genetic programs become activated, resulting in cell-type-specific biological responses. Regulation of specific cellular responses to extracellular stimuli is primarily determined by integration of the various components involved in the signal transduction pathway. There are several mechanisms by which cells modulate STAT signaling. For example, JAK family members associate selectively with specific cytokine receptor superfamily members.9,11 Thus, depending on ligand and cell type, multiple STAT family members may become activated. Since STAT proteins homodimerize or heterodimerize, the level of signaling diversity increases. In addition, the temporal duration of STAT activation is another potential mechanism by which to modulate the response. In normal signaling, activation of STATs occurs rapidly; however, the induction is transient. Finally, activation of parallel signaling pathways, such as mitogen-activated protein (MAP) kinases,3 also contributes to the complexity of signal transduction.

Aberrant STAT Activation in Neoplastic Transformation

Since STAT proteins regulate normal mitogenic responses, researchers have begun to investigate whether deregulated activation of STATs contributes directly to cellular transformation. In contrast to normal signaling, aberrant receptor activation or protein tyrosine kinase (PTK) activity induces constitutive STAT signaling in oncogenesis. The first genetic evidence implicating aberrant STAT activation in the development of neoplasias was derived from studies of signal transduction in fruit flies. A Drosophila JAK homolog with a lethal gain-of-function mutation that results in hyperactive JAK kinase activity causes leukemia-like defects to develop.12,13 Dominant suppressors of this phenotype map to loss-of-function mutations in the Drosophila homolog of a mammalian STAT gene.14,15 Thus, these studies suggest that deregulated JAK kinase activity, resulting in constitutive activation of a Drosophila STAT, directly leads to the formation of hematopoietic malignancies.

In mammalian cells, the original report demonstrating that Stat3 DNA binding is constitutively activated in stably transformed fibroblast cells linked activation of the oncogenic Src tyrosine kinase to activation of one STAT family member, Stat3.16 In these studies, a good correlation was observed between activation of Stat3 and oncogenic transformation by Src. This observation, which was confirmed independently by other investigators,17,18 raised the possibility that other diverse oncoproteins of the receptor or nonreceptor PTK family may also activate STATs during oncogenic transformation. This prediction has been borne out in numerous studies by many laboratories, and Table 1 lists the viral16-27 and cellular17,19,24,26-30 oncogenes that activate specific STAT family members.

Significantly, recent reports provide direct evidence that constitutive STAT activation has a causal role in oncogenesis.31,32 Constitutive Stat3 DNA-binding activity induced by the Src oncoprotein results in stimulation of Stat3-dependent gene expression.25,31,32 Moreover, interference with Stat3 signaling by co-expression of dominant-negative forms of the Stat3 protein blocks the transforming ability of Src.31,32 In contrast, co-expression of dominant-negative Stat3 together with the Ras oncoprotein, which does not activate Stat3, does not block Ras-induced transformation. The combined results of these studies demonstrate that activation of STAT signaling is one pathway required for cellular transformation by specific classes of oncoproteins with PTK activity. STAT proteins presumably contribute to oncogenesis by eliciting permanent changes in the genetic program required for the initiation or maintenance of transformation.

Activation of STAT Signaling in Human Cancer

Overexpression and/or elevated kinase activity of Src, epidermal growth factor receptor, and other PTKs is associated with various human cancers. As a consequence, a growing body of evidence indicates that abnormal STAT signaling in response to hyperactive PTK activity is frequently detected in human tumors in association with the progression of oncogenesis (Table 2).33 In particular, increased levels of Src and epidermal growth factor receptor or their associated kinase activities correlate with carcinoma of the breast. In surveys of normal breast epithelial or breast carcinoma cell lines, studies reveal that Stat3 is activated with high frequency in the carcinoma cell lines but not in the cell lines derived from normal epithelium.21,34 In addition, elevated Stat3 activity has been detected in primary breast tumors35 (R. Garcia and R. Jove; J. Bromberg and J. Darnell; unpublished data, 1999). Other solid tumors shown to possess aberrant STAT activation include head and neck squamous cell carcinoma,36 ovarian carcinoma, and skin melanomas (R. Garcia, R. Catlett-Falcone, and R. Jove, unpublished results, 1999). STAT activation also correlates with the progression of diverse hematopoietic malignancies (Table 2), such as various leukemias24,28,37-42 and lymphomas.42-48 In addition, Stat3 is frequently activated in both multiple myeloma cell lines and tumors derived from patient bone marrows.49

Recently, the role of STAT signaling as it relates to the pathogenesis of multiple myeloma has been elucidated.49 Malignant progression of multiple myeloma depends on the IL-6 signaling pathway for the growth and survival of myeloma cells.50,51 Previous studies have correlated elevated levels of the antiapoptotic regulatory protein, Bcl-xL, with IL-6 signaling in myeloma.52 Results from this recent study demonstrate that constitutive activation of Stat3 signaling, an important component of the IL-6 pathway,3 directly contributes to the induction of Bcl-xL gene expression. Moreover, interfering with Stat3 activation by blocking components of the IL-6 signaling pathway inhibits Bcl-xL expression and leads to apoptosis. Thus, constitutive activation of Stat3 signaling by IL-6 induces the expression of the Bcl-xL gene through Stat3-dependent gene regulation and thereby prevents apoptosis.49 These results demonstrate that Stat3 activation is required for promotion of tumor cell survival and directly contributes to the malignant progression of multiple myeloma by allowing accumulation of long-lived plasma cells.

Rationale Behind Targeting STAT Signaling for Drug Discovery

The implication of the above studies is that aberrant STAT signaling contributes to a permanent alteration in the genetic program of cells that ultimately results in malignant progression. Disruption of Stat3 function using a dominant-negative Stat3 protein blocks transformation of fibroblasts by the Src oncoprotein.31,32 Consistent with the results of these studies, growth and survival of multiple myeloma requires Stat3-dependent signaling.49 Since STAT proteins are involved in regulating fundamental biological processes, including apoptosis and cell proliferation, disruption of STAT signal transduction is a novel approach to block malignant progression in a wide variety of human tumors that depend on activation of STATs for tumorigenesis.

Although the STAT family is highly structurally conserved, there are distinct differences in both primary sequence and function. Targeted disruption of the Stat1, Stat4, Stat5a, Stat5b, and Stat6 genes in mice demonstrates tissue specificity with respect to function for each family member.2 In the case of Stat2 and Stat3, homozygous deletion of the gene encoding either protein is embryonic lethal. These results demonstrate that while the STAT family members share common structural features, they do not substitute for each other functionally. The nonredundant role of STAT family members is due in large part to the diversity of STAT signaling discussed above. The specificity imparted by ligand/receptor signaling results in divergent signaling pathways depending on the profile of activated STAT proteins. Thus, the lack of functional overlap among the STAT family members is an important criterion for development of inhibitors that specifically disrupt a particular STAT signaling pathway.

A critical test that must be met in order for STATs to be candidates for therapeutic intervention is whether loss of function of the target molecule is generally cytotoxic. Specifically, the results of disrupting Stat3 signaling in normal mouse fibroblasts demonstrate that inhibition of Stat3 activation is not deleterious to all normal cell growth.31,32 Thus, normal cellular functions may not be grossly impaired by blocking Stat3 signaling, perhaps due in part to low levels of residual Stat3 signaling being sufficient for sustaining normal biological processes. One possible explanation for the sensitivity of transformed cells compared to normal cells is that tumor cells may have become irreversibly dependent on STAT signaling to sustain their growth and survival, while normal cells may be able to use alternative pathways to compensate for loss of STAT signaling.

Relevance of STAT Activation to Chemotherapy Response

One of the goals in the treatment and prevention of cancer is to minimize the toxic effects of the chemotherapeutic regimen while simultaneously eradicating the tumor cells. Many types of tumors, particularly aggressive cancers, are initially refractory to chemotherapy or eventually become resistant to the therapies. One of the mechanisms of tumor cell killing by anticancer agents involves programmed cell death (apoptosis). Earlier studies have indicated that elevated Bcl-xL expression induces resistance to some chemotherapeutic drugs that use apoptosis pathways for tumor cell killing.53,54 As discussed above, myeloma tumor cells with constitutively activated Stat3 signaling and elevated Bcl-xL expression are resistant to apoptosis49 and hence are predicted to be resistant to chemotherapy drugs that utilize apoptosis pathways.

Minimizing the side effects of chemotherapy while maximizing the antitumor activity has been difficult to achieve. Thus, one potential advantage to disrupting STAT signaling in tumors is that inactivation of STATs may sensitize the STAT-dependent cells to chemotherapeutic agents. At the same time, the undesirable side effects of more aggressive anticancer treatments may be avoided if sensitization allows for lower doses of these potent agents to be administered. Because blocking STAT signaling inhibits Bcl-xL expression and induces apoptosis in myeloma cells,49 therapeutic strategies that disrupt STATs may confer sensitivity to chemotherapeutic drugs. Thus, development of selective inhibitors of STAT activation for use in combination therapy with more conventional chemotherapy appears to be a promising area in the field of novel anticancer therapeutics.

Targeting STATs by Gene Therapy

While gene therapy approaches to cancer treatment are still in relatively early stages of development, gene therapy offers a powerful experimental tool to establish "proof of principle" that a particular molecular pathway is a valid target for cancer treatment. Stat3 is an excellent example of the power of this approach. The studies summarized above point to a critical role for activated Stat3 signaling in human cancer, and they suggest that Stat3 is a novel molecular target for cancer therapies. To evaluate Stat3 as a potential target for cancer therapy, recent studies have used gene therapy approaches to block Stat3 signaling in a mouse model of melanoma.55 Using a mouse melanoma cell line containing constitutively activated Stat3 to induce tumors in syngeneic mice, vector DNA encoding a dominant-negative form of Stat3 was delivered intratumorally by electroinjection. Results show significant inhibition of tumor growth and tumor regression as a result of the gene therapy. This block in tumorigenesis is associated with massive apoptosis of the melanoma tumor cells in vivo. These findings are consistent with the earlier observations that blocking Stat3 signaling induces apoptosis in human myeloma tumor cells in vitro49

These gene therapy studies demonstrate that blocking Stat3 signaling induces potent antitumor activity in vivo, and they provide evidence that Stat3 is a promising target for therapy of human cancers harboring activated Stat3. Based on other studies demonstrating antitumor effects of cytokine-based genetic immunotherapy,56,57 it is likely that combination gene therapy with antitumor cytokines and Stat3 dominant-negatives will have more potent activity than either approach alone. These Stat3 gene therapy studies55 establish "proof of principle" that Stat3 is a valid molecular target for cancer therapy, not only by genetic approaches, but also by small molecule inhibitors of Stat3.

Methods for Screening Compounds That Disrupt STAT Signaling

Detailed elucidation of the structure-function relationships of STAT proteins will facilitate the rational design of molecules capable of disrupting the critical functions of STAT proteins. Augmenting the research goal of designing such molecules is the recent determination of the crystal structures of Stat1 and Stat3 bound to their DNA consensus sequences.58,59 The requirement of tyrosine phosphorylation for STAT dimerization and activation offers tyrosine kinases and SH2-pY interactions as targets for the design of selective inhibitors of STAT function. In addition, other essential structural features, such as the DNA binding and transactivation domains (Fig 1), are also potential targets for functional disruption.

There are numerous approaches to identifying small molecules that will disrupt STAT signaling. Many of these strategies are based on high-throughput screening to identify compounds that are selective for inhibiting specific STAT functions in vitro or in vivo. For in vitro screens, the ability of compounds to disrupt STAT dimerization or DNA binding can be assessed by using modifications of conventional assays that directly measure these biochemical properties. Specifically, DNA-binding activity can be assayed using synthetic DNA oligonucleotides corresponding to authentic STAT binding sites in the promoters of genes.16,21 In vivo screens can be designed to detect disruption of STAT-specific gene regulation. Specifically, "reporter" mini-genes that are dependent on STAT signaling for expression of proteins that can be conveniently detected based on biochemical properties such as light emission or colorimetric intensity can be designed.32 Sensitive instruments capable of detecting and quantifying these biochemical properties of the reporter proteins directly measure the ability of a compound to selectively inhibit STAT signaling. Another important in vivo assay is evaluation of the effect of compounds on oncogenic properties of human tumor cell lines in cultures. The goal of such screens is to identify compounds that effectively block the growth of tumor cells with minimal toxicity toward normal cells. Finally, the most promising compounds will need to be tested in animal models of relevant human cancers for efficacy and lack of toxicity. At the end of these studies, it is expected that much will be learned about the antitumorigenic activity as well as the underlying molecular mechanisms of action of compounds that disrupt STAT protein function. Successful compounds in the most rigorous animal studies will be candidates for human clinical trials.

Conclusions

STATs participate in regulating normal cellular processes, converting stimuli from cytokines and growth factors into appropriate biological responses. To accomplish this, STATs regulate specific genetic programs that coordinate the cellular effectors mediating these biological outcomes. Indeed, STATs have been reported to participate in the regulation of development, cell proliferation, differentiation, and apoptosis in addition to specialized cellular functions. Therefore, there exists the potential for aberrant STAT signaling to adversely affect the outcomes of these fundamental biological processes and thereby contribute to oncogenesis. In recent years, a multitude of studies associating aberrant activation of STATs with neoplastic transformation point to this signaling pathway as having considerable promise for therapeutic intervention.

Future Directions

The advances made in treating human neoplasias have formerly relied on development of cytotoxic agents that would, in the best-case scenario, eradicate the tumor before healthy cells succumb to the effects of chemotherapy. New approaches in drug discovery and design are moving toward developing antioncogenic compounds that will result in remission or complete regression of the disease with decreased toxicity. These agents are designed to attack cancer cells at their molecular "Achilles heel." In other words, research is being devoted to developing chemotherapeutic agents that target specific molecular pathways essential for cancer cell survival and proliferation but that are less essential for normal cellular functions. Disruption of STAT signaling holds the potential for effecting this type of favorable outcome.

A large percentage of cancers fall into the category of sporadic rather than inherited types. Discovery of the molecular mechanisms responsible for the initiation and progression of these sporadic forms of human cancer is ultimately required in order for anticancer treatment to be safer and more effective. Efforts are underway to investigate the mechanisms by which aberrant STAT activation influences the progression of neoplastic transformation. Clinically important benefits from the discovery of the contribution of STAT activation to oncogenesis include development of new diagnostic and prognostic assays based on the molecular STAT profile of tumors. Furthermore, because STAT activation has been shown to be required for oncogenic transformation, discovery and development of novel inhibitors of STAT signaling hold significant promise for providing more effective treatment for a wide variety of cancers at various stages of malignant progression.

Appreciation is expressed to members of our laboratories for stimulating discussions and to Moffitt Cancer Center, the Angela Musette Russo Foundation, and the National Cancer Institute for their generous support.

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Glossary

Apoptosis: the cellular process, also known as programmed cell death, in which the cell undergoes a series of molecular events leading to morphological changes such as DNA fragmentation, chromatin condensation, nuclear envelope breakdown, and cell shrinkage.

Bcl-xL : a member of the Bcl-2 (B-cell lymphoma) family of proteins involved in regulating the response of the cell to apoptosis; Bcl-xL prevents programmed cell death.

DNA consensus sequence: a specific nucleotide motif found in the promoters of genes to which a transcription factor binds through interaction of the protein¡¯s DNA-binding domain with the nucleotide sequence.

Dominant-negative protein: a protein that has been genetically altered so that when expressed in a cell interferes with the function of the endogenous wild-type protein.

Interleukin 6 (IL-6): cytokine involved in regulating growth, survival, and function of cells.

Janus kinase (JAK): a member of a closely related family of nonreceptor tyrosine kinases that transfers a phosphate moiety to tyrosine on recipient proteins.

Phosphotyrosine: modification of the tyrosine amino acid residue in which a phosphate group has been transferred to the hydroxyl group.

Promoter: region of gene preceding the protein coding sequence that contains nucleotide sequence elements to which transcription factors bind and regulate gene expression.

Protein tyrosine kinase (PTK): signal transduction molecule possessing an enzymatic function that transfers phosphate moieties to tyrosine on recipient proteins and thereby modulates the activity of the target protein.

Signal transducer and activator of transcription (STAT): member of a family of proteins that, when activated by PTKs in the cytoplasm, migrate to the nucleus and activate gene transcription.

Signal transduction: the biochemical process involving transmission of extracellular stimuli, via cell surface receptors through a specific and sequential series of molecules, to genes in the nucleus resulting in specific cellular responses to the stimuli.

Src-homology 2 domain (SH2): a specific protein structural motif among signaling molecules that recognizes and binds to phosphotyrosine moieties, creating sites of protein-protein interaction.

Src tyrosine kinase (Src): a member of a closely related family of nonreceptor tyrosine kinases that participate in signal transduction by phosphorylating downstream effectors; the src gene is the first viral oncogene and was identified in Rous sarcoma virus.

Syngeneic mice: mice derived from a genetically identical background.

Transcriptional activation: the induction of gene expression via the interaction of regulatory proteins with the promoter elements of target genes.

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THE ENEMY WITHIN: KEEPING SELF-REACTIVE T CELLS AT BAY IN THE PERIPHERY

THE ENEMY WITHIN: KEEPING SELF-REACTIVE T CELLS AT BAY IN THE PERIPHERY

Lucy S.K. Walker & Abul K. Abbas about the authors

Preface
The remarkable capacity of the mammalian immune system to coordinate deadly attacks against numerous invading pathogens, yet turn a blind eye to self-tissues continues to fascinate immunologists. It has been clear for some time that immune cells capable of recognizing self-proteins exist in normal individuals without seemingly causing harm. The 'peripheral tolerance' mechanisms that keep these cells in check are the focus of intense research, not least because defects in these pathways might cause autoimmune diseases. In this review, new developments in our understanding of peripheral tolerance are discussed.

Summary
Thymic deletion clearly fails to eliminate all self-reactive T cells; therefore, peripheral tolerance mechanisms are required to prevent autoimmune disease.
Peripheral tolerance mechanisms can be subdivided into those that act directly on the responding T cell (T-cell intrinsic) and those with an indirect effect (T-cell extrinsic).
T-cell intrinsic mechanisms of tolerance to self-antigens include ignorance, anergy, phenotypic skewing and activation induced cell death.
T-cell extrinsic mechanisms of self-tolerance have received much recent press, and include control of the phenotype of the dendritic cell presenting self-antigen, and the involvement of regulatory T cells.
How infections might interfere with pathways of tolerance and permit induction of autoimmune disorders is an ongoing area of research.

Nature Reviews Immunology 2, 11 -19 (2002)

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(Article, p.45; News and Views)

p53 mutant mice that display early ageing-associated phenotypes

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.

http://www.nature.com/nlink/v415/n6867/abs/415045a_fs.html

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Identification of a host protein essential for assembly of immature HIV-1 capsids

To form an immature HIV-1 capsid, 1,500 HIV-1 Gag (p55) polypeptides must assemble properly along the host cell plasma membrane. Insect cells and many higher eukaryotic cell types support efficient capsid assembly, but yeast and murine cells do not, indicating that host machinery is required for immature HIV-1 capsid formation. Additionally, in a cell-free system that reconstitutes HIV-1 capsid formation, post-translational assembly events require ATP and a subcellular fraction, suggesting a requirement for a cellular ATP-binding protein. Here we identify such a protein (HP68), described previously as an RNase L inhibitor, and demonstrate that it associates post-translationally with HIV-1 Gag in a cell-free system and human T cells infected with HIV-1. Using a dominant negative mutant of HP68 in mammalian cells and depletion¨Creconstitution experiments in the cell-free system, we demonstrate that HP68 is essential for post-translational events in immature HIV-1 capsid assembly. Furthermore, in cells the HP68¨CGag complex is associated with HIV-1 Vif, which is involved in virion morphogenesis and infectivity. These findings support a critical role for HP68 in post-translational events of HIV-1 assembly and reveal a previously unappreciated dimension of host¨Cviral interaction.

http://www.nature.com/nlink/v415/n6867/abs/415088a_fs.html

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¡¡¡¡John J. O'Shea, Averil Ma & Peter Lipsky about the authors

Preface
Cytokines have crucial functions in the development, differentiation and regulation of immune cells. As a result, dysregulation of cytokine production or action is thought to have a central role in the development of autoimmunity and autoimmune disease. Some cytokines, such as interleukin-2, tumour-necrosis factor and interferons ¡ª ostensibly, the 'bad guys' in terms of disease pathogenesis ¡ª are well known for the promotion of immune and inflammatory responses. However, these cytokines also have crucial immunosuppressive functions and so, paradoxically, can also be 'good guys'. The balance between the pro-inflammatory and immunosuppressive functions of these well-known cytokines and the implications for the pathogenesis of autoimmune disease is the focus of this review.

Summary
Cytokines have essential roles in immune cell development, immunoregulation and immune effector functions.
Cytokines such as interleukin (IL)-2, tumour-necrosis factor (TNF) and the interferons are well known to have immunostimulatory and pro-inflammatory actions. However, the same cytokines also have unexpected, but essential, immunosuppressive actions.
IL-2 has essential functions in constraining lymphocyte growth by promoting apoptosis. Regulatory T cells that express the IL-2 receptor -chain have also been intensively studied. Deficiency of these cells can result in autoimmunity, but the exact role of IL-2 in the physiology of these cells is unknown.
Despite TNF's role as the prototypic cytokine that mediates proinflammatory responses, it is now clear that its in vivo role is complex. Experimental models of disease show that immune-mediated disease, including arthritis, can occur in the absence of TNF. Models of diabetes have shown that TNF can worsen or improve disease, depending on the timing and duration of exposure to this cytokine.
Interferons have essential functions in host defence and promote cell-mediated immunity. Type 1 interferons, in particular, have been used to treat autoimmune diseases, including those characterized by T-helper (TH)1-mediated pathology. Type 1 interferons can inhibit secretion of IL-12 and inhibit its action. Type 2 interferon (interferon-) and other cytokines upregulate the expression of a class of feedback inhibitors known as suppressors of cytokine signalling (SOCS). Mice deficient in Socs1 have fatal, interferon-dependent, inflammatory disease.

http://www.nature.com/nrilink/v2/n1/abs/nri702_fs.html

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Distinguishing Th1 and Th2 Cells

Various techniques differentiate helper T cell subsets
By Jeffrey M. Perkel

Schematic representation of cytokines influencing the development of antigen-activated naive CD4+ T cells into Th1 and Th2 cells

The human body is constantly under siege. It must defend itself from a whole host of bacterial, parasitic, and viral invaders, not to mention rogue cancerous cells. The immune system is the primary line of defense in this game of chess, recognizing and ignoring "self" antigens, while vigorously attacking foreign ones. T lymphocytes, the strategists in this game, both direct the responses of the rest of the immune system and play an active role in it. T cells orchestrate the immune response via the production of cytokines--secreted proteins that instruct other cells to behave in specific ways. Scientists have devoted a great deal of time and effort to understanding the development and differentiation of T lymphocytes because of both the pivotal role T cells play in directing the immune response and the interesting developmental paradigms T cells represent.
T cells may be broadly classified as either helper T cells (Th cells, CD4+) or cytotoxic T cells (Tc cells, CD8+). In 1986, T.R. Mosmann, R.L. Coffman, and colleagues observed that individual clones of helper T cells could be separated into two classes depending upon the specific cytokines the cells secrete in response to antigenic stimulation.1 Th1 cells primarily produce interferon (IFN)-g and interleukin (IL)-2, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. The two helper T cell classes also differ by the type of immune response they produce. While Th1 cells tend to generate responses against intracellular parasites such as bacteria and viruses, Th2 cells produce immune responses against helminths and other extracellular parasites.2,3 Interestingly, the cytokines produced by each Th subset tend to both stimulate production of that Th subset, and inhibit development of the other Th subset. That is, IFN-g produced by Th1 cells has the dual effect of both stimulating Th1 development, and inhibiting Th2 development. Th2-secreted IL-10 has the opposite effect.4

There is perhaps no more dramatic demonstration of the functional consequence of the diametrically opposing roles of Th1 and Th2 cells than the ability of inbred mouse strains to respond to infection with Leishmania major, an intracellular parasite. Most inbred mouse strains (such as B10.D2) respond to L. major infection with a Th1-like response, clearing the infection. In contrast, BALB/c strains, which respond with a Th2 response, are unable to do so, and ultimately succumb to infection.5

It is unclear as to how newly minted helper T cell precursors can be induced to differentiate into Th1 or Th2 cells in vivo. Cytokines clearly play an important role in the development and/or maintenance of Th lineages. But there is an ongoing debate about exactly what that role is, says Steve Reiner of the University of Pennsylvania. Reiner identifies two competing models: instruction and selection. The instruction model holds that naive T cells are instructed to differentiate into either Th1 or Th2 cells by virtue of the cytokine environment that surrounds them. That is, if naive T cells find themselves in the presence of IL-12, they will differentiate into Th1 cells, whereas IL-4 will stimulate Th2 differentiation. The selection model suggests that the cells randomly "choose" a differentiation path, and the cytokines maintain and select for T cell subsets once they have already committed to a particular fate.

Reiner's lab identifies and distinguishes Th cell subsets using intracellular cytokine staining (ICS). This technique, developed by Andreas Radbruch and colleagues at the University of Cologne, Germany, involves treating cells with Brefeldin A to prevent secretion of intracellular cytokine protein.6 The cells are then permeabilized, tagged with fluorescently labeled antibodies to specific cytokines, and counted using flow cytometry. According to Reiner, the advantage of this technique is that it analyzes the cytokine production of each individual cell as opposed to analyzing the aggregate cytokine production of the entire cell population. Thus, it is possible to see what collection of cytokines each cell is producing. BD Pharmingen of San Diego currently produces an Intracellular Cytokine Staining "starter" kit, containing fixing and permeabilization solutions, as well as labeled antibodies to IL-2, IFN-g, and tumor necrosis factor (TNF)-a. The company also supplies a wide range of other labeled antibodies to supplement this kit, such as antibodies against the various Th2 cytokines. Biosource International of Camarillo, Calif., offers ICScreen? kits for ICS of Th1/Th2 cytokines as well. These kits block cytokine secretion in the Golgi with the Na+ ion-dependent transport inhibitor monensin (ICBlock?). Caltag Laboratories Inc. of Burlingame, Calif., offers the FIX & PERM? cell permeabilization kits and CYTO-IC antibodies designed for ICS.

The major drawback to ICS is that the cells must be killed in order to stain them. Therefore, it is not possible to use ICS to enrich for specific cytokine-producing cell populations for use in downstream applications. In 1995, Radbruch and colleagues described a method to analyze and sort live cells secreting either IgM or IFN-g.7 The authors developed an affinity matrix for the secreted molecule by biotinylating the cell surface, and then binding an antibody-avidin conjugate to it. In a recent publication in Immunity, Kenneth Murphy of the Washington University School of Medicine in St. Louis, and Radbruch (now at Deutsches Rheuma-Forschungszentrum in Berlin, Germany), described a modification of this method, effectively circumventing the shortcomings of ICS.8 The authors replaced the biotin-avidin interaction with a bifunctional antibody conjugate, able to bind to the ubiquitous cell surface marker, CD45, as well as to IL-4. Treatment of the cells with this conjugate created a "high-capacity surface matrix" to bind secreted IL-4. IL-4-secreting cells were identified by the addition of a second anti-IL-4 antibody, conjugated to phycoerythrin (PE). Finally, secreting cells were purified by the addition of anti-PE antibodies conjugated to magnetic microbeads. Miltenyi Biotec Inc. of Auburn, Calif., offers kits based upon this technique, for the enrichment and detection of cells secreting IL-2, IL-4, IL-10, and IFN-g. According to Roger Burger, product manager at Miltenyi Biotec, the IFN-g detection antibody is available in both PE- and FITC-labeled forms, enabling researchers to select for secretion of both IFN-g and IL-10 on the same cell, for example.

Researchers in the lab of Richard M. Locksley at the University of California, San Francisco, use an alternative means of quantifying cytokine-producing cells called the Elispot assay. Cells are cultured in microwell plates coated with an appropriate antibody. As the cells secrete cytokines, these proteins are captured by the nearby plate-bound antibodies. After some period of time, the cells are washed away, alkaline phosphatase-conjugated secondary antibody is added, and the captured cytokines are detected via precipitation of a detection reagent. This produces spots that can be counted, thereby quantifying the number of secreting cells in the assay. Commenting on the differences between ICS and Elispot, Locksley observed that Elispot "tells you the precursor frequency and identifies spontaneously-secreting cells. Intracellular cytokine staining involves restimulating cells, permeabilizing them with saponin and hoping to catch cytokine captured in the ER after poisoning the cells with Brefeldin A. We all do it, but it is relatively insensitive." Elispot detection systems and reagents are offered by R&D Systems of Minneapolis, Biosource International, Mabtech of Nacka, Sweden, and Diaclone of Besan?on Cedex, France. BD Pharmingen, in collaboration with Cellular Technology Ltd. of Cleveland, Ohio, offers both Elispot reagents and high-throughput instrumentation (CTL's ImmunoSpot? Series One Analyzer).

Detecting Transcripts
Though the mechanisms of Th differentiation in vivo are still a mystery, the differentiation of cultured T cells can be readily accomplished in the laboratory. For example, Suneet Agarwal and Anjana Rao, of the Center for Blood Research in Boston, produced the two Th lineages using a pair of mutually exclusive selection conditions.9 Starting with naive (Mel14hi) CD4+ lymphocytes obtained from the spleen and lymph nodes of mice, these authors generated Th1 cells by treating the cells with IL-12 and an antibody against IL-4 (to remove IL-4 from the media). They generated Th2 cells using IL-4, and antibodies against both IFN-g and IL-12. After two weeks, the authors analyzed the cytokine expression profile of each culture using a RiboQuant multiprobe RNAse protection assay (RPA) kit from BD Pharmingen. As expected, after growth under the highly polarizing conditions used in the experiment, the two cultures exhibited a mutually exclusive constellation of cytokines that identified them as either Th1 or Th2. Commenting on the advantages of using RPA to detect transcript levels, Rao says RPA results are "linearly related to the steady-state transcript level, and provide a much more sensitive way of assessing gene transcription [than Northern blots]." Rao adds that, although the RPA kit cannot be used to quantify the level of primary transcript, the technique provides "the next best thing, which is the steady-state level of processed transcript in the cytoplasm."
Th1- and Th2-specific cytokine transcripts may also be detected using RT-PCR. Biosource International offers two Th1/Th2 CytoXpress? multiplex-PCR kits, including amplification reagents (except a thermostable polymerase) and primers. Set 1 simultaneously detects the presence of IFN-g, IL-2, IL-4, and IL-10; set 2 detects each of these, as well as IL-5, IL-12p40, and IL-13. Both sets include GAPDH as a control, and both human and murine versions are available. Biosource also offers PrimeScreen? primer pairs to detect individual cytokines as well.

R&D Systems offers an alternative mRNA detection method with its Quantikine mRNA detection system.10 This system uses two separate oligonucleotide probes: biotin-labeled capture oligonucleotides, and digoxigenin-labeled detection oligonucleotides. RNA samples are hybridized to both probes, and captured to streptavidin-coated microtiter plate wells via the biotin moiety. An anti-digoxigenin alkaline phosphatase conjugate and a colorimetric substrate are used to detect the specific transcripts. According to Leena Martel, a marketing representative at R&D Systems, the Quantikine mRNA kits were originally designed for those customers more comfortable with ELISA kits than with radioactive Northern blots and RPAs. The result is an ELISA-type assay with sensitivity akin to that of a Northern blot, yet which may be performed in less than five hours. One potential drawback of the Quantikine assay is that, for all its sensitivity, it cannot be used to assess either transcript integrity or length, features readily determined by Northern blotting.

Chemicon International's XpressPack? systems function as a cross between Quantikine and RT-PCR techniques. Cytokine gene-specific transcripts are amplified using biotin-labeled PCR primers. The amplified DNA is then denatured and hybridized to a 96-well plate coated with a gene-specific probe. This hybridization is detected by addition of either horseradish peroxidase- or AquaLite?-conjugated streptavidin. XpressPack kits contain the oligonucleotide-coated plates, biotin-conjugated primers, and a positive control; the detection reagents must be purchased separately. Kits are available for the detection of IL-2, IL-4, IL-10, and IFN-g. Tony Endozo, who helped develop the XpressPack kits for Chemicon, notes that the primers included in the kit are designed to be mRNA-specific, so researchers can be certain that amplified products reflect gene expression, and not the presence of genomic DNA. Courtesy of Sigma-Genosys

Nylon membrane-based microarrays present a relatively inexpensive method for multiplexed cytokine transcript detection. These assays provide the benefits of microarrays without the tremendous investment in new technology required for microscope slide-based microarray analysis. In addition, unlike glass arrays, membrane arrays can be stripped and reprobed several times. BD-Pharmingen's RiboScreen? human-1 membrane contains an array of 289 separate human genes on a nylon membrane. Every gene that can be quantified using RiboQuant is represented on the RiboScreen membrane, enabling RiboScreen to be used as an initial screening method prior to RiboQuant analyses. Sigma-Genosys of The Woodlands, Texas and R&D Systems also offer a nylon membrane-based array approach: the Panorama? mouse cytokine gene array contains 514 cDNAs plus controls, while the human cytokine gene array contains 375 genes plus controls. The Common Cytokine-1 GEArrays from SuperArray of Bethesda, Md., contain 23 cytokine genes spotted in duplicate, available for both mouse and human genes. The LifeGrid?, from Incyte Genomics of Palo Alto, Calif., also marketed as the ULTRArray by Ambion of Austin, Texas, features nearly 8,400 human cDNAs. The GeneFilter? from Research Genetics of Huntsville, Ala., contains 5,184 murine or human genes and ESTs. BD Biosciences-CLONTECH of Palo Alto, Calif., offers its popular Atlas? microarrays in a nylon membrane format, with human, mouse, and rat versions, each containing 1,176 genes.

Detecting Proteins
Researchers interested in quantifying the cytokines secreted by a culture have a number of options. Enzyme-linked immunosorbent assays (ELISAs) are commonly used for this purpose. A comprehensive listing of companies selling antibodies directed against cytokines, which can be used in ELISAs, was previously published in The Scientist.11 Biosource International's ELISA-variant CytoTrap? cell stimulation assay kits can be used to detect secreted Th1/Th2 cytokines. In a CytoTrap assay, cells are grown in an antibody-coated microplate. After stimulation and growth, the cells are washed away, and the secreted cytokines are detected as in a standard ELISA. Unfortunately, purchasing the ELISA reagents necessary for a number of cytokines can be costly. BD Pharmingen offers the human Th1/Th2 cytokine cytometric bead array (CBA) kit, which is a multiplexed flow cytometric assay designed to simultaneously test for IL-2, IL-4, IL-5, IL-10, TNF-a, and IFN-g. The kit uses fluorescent capture beads coated with antibodies against an individual cytokine. The different beads have discrete fluorescent intensities, so they may be distinguished in the FL3 channel of a flow cytometer. Thus, there are six discrete peaks in the FL3 channel, corresponding to each set of capture beads. These beads are mixed with cell culture medium, into which cytokines have been secreted, and then with phycoerythrin (PE)-conjugated secondary antibodies. Their intensity can then be detected in the FL2 channel. According to Deanna Murphy, technical service representative at BD Pharmingen, each bead in the CBA kit acts like an individual ELISA well; the practical implication of this is that each bead in the experiment acts as a replicate "well", so experiments do not need to be set up in duplicate or triplicate.

Courtesy of Upstate Biotechnology

LabMAP? technology from Luminex Corp. of Austin, Texas, also uses beads with differing fluorescent intensities. But rather than using a flow cytometer, results are obtained using Luminex's detection system. The Beadlyte? multi-cytokine detection systems from Upstate Biotechnology of Lake Placid, N.Y.; Bio-Plex? kits from Bio-Rad of Hercules, Calif.; Multiplex Antibody Bead kits from Biosource International; and LINCOplex? cytokine assays from LINCO Research Inc. of St. Charles, Mo., are all based on LabMAP technology. Courtesy of Upstate Biotechnology

Beadlyte cytokine detection systems are sandwich immunoassays performed on unique fluorescent beads, which contain a precise distribution of two fluorescent dyes, and a specific cytokine capture antibody linked to its surface. The fluorescent bead sets are incubated with a biological sample. A biotinylated cytokine reporter antibody is then used to identify the captured cytokine bound to the specific fluorescent bead. The reaction is detected by adding a streptavidin-phycoerythrin conjugate to the reaction mixture and read in a Luminex 100 instrument.

BioErgonomics Inc. of St. Paul, Minn., offers MultiFlow? kits capable of detecting up to three different cytokines at once, using paramagnetic beads. Unlike other systems, these beads are not fluorescent; the analytes are identified using fluorescently tagged antibodies instead. Because the light-scattering properties of these beads are distinct from cells, the beads can be distinguished from cells during flow cytometry. This allows researchers to mix beads with the cells and analyze both at the same time. Multiplexed assays will be discussed in greater detail in the May 28, 2001, issue of The Scientist.

Helper T cells play a central role in directing the immune response. Whether an antigen elicits a Th1- or Th2-type response has a profound effect on the ability of the body to clear the infection. Scientists will therefore continue to use the tools discussed in this article to study helper T cells as models for cellular development and differentiation.

Jeffrey M. Perkel can be contacted at jperkel@the-scientist.com.
References
1. T.R. Mosmann, et al., "Two types of murine helper T cell clone: I. Definition according to profiles of lymphokine activities and secreted proteins," Journal of Immunology, 136:2348-57, 1986.

2. A. O'Garra, N. Arai, "The molecular basis of T helper 1 and T helper 2 cell differentiation," Trends in Cell Biology, 10:542-50, Dec. 2000.

3. T.R. Mosmann, R.L. Coffman, "Th1 and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties," Annual Review of Immunology, 7:145-73, 1989.

4. A.K. Abbas, et al., "Functional diversity of helper T lymphocytes," Nature, 383:787-93, 1996.

5. S.L. Reiner, R.M. Locksley, "The regulation of immunity to Leishmania major," Annual Review of Immunology, 13:151-77, 1995.

6. M. Assenmacher, et al., "Flow cytometric determination of cytokines in activated murine T helper lymphocytes: Expression of interleukin-10 in interferon-g and in interleukin-4-expressing cells." European Journal of Immunology, 24:1097-101, 1994.

7. R. Manz, et al., "Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix," Proceedings of the National Academy of Science, 92:1921-5, 1995.

8. W. Ouyang, et al., "Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment," Immunity, 12:27-37, 2000.

9. S. Agarwal, A. Rao, "Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation," Immunity, 9:765-75, 1998.

10. H.E. Sussman, "A quantum leap in mRNA quantitation," The Scientist, 14[21]:22, Oct. 30, 2000.

11. B. Sinclair, "The divine cytokine," The Scientist, 14[7]:36, April 3, 2000.

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