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Relationship: 2026


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Suppression of STAT5 binding leads to Suppression of IL-4 production

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response adjacent High High Yasuhiro Yoshida (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Mixed High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

A STAT5 binding site (TTCATGGAA) has been identified in intron 2 of the Il4 gene, near HSII (89-Hural-2000). Another potential STAT5 binding site (TTCTAAGAA), conserved between mouse and human, and was found near HSIII. Stat5A binds to the sites near HSII and HSIII, which could provide a mechanism through which STAT5A mediates Il4 gene accessibility and participates in the induction of IL-4 production. Enhanced STAT5 signaling results in a larger proportion of cells producing IL-4. A consensus STAT site that preferentially associates with STAT5 contributes to its enhancer activity in mast cells. The intron element plays a role in acquiring and/or maintaining the IL-4 gene locus in a demethylated state in IL-4-producing cells.

Constitutive active STAT5A (STAT5A1*6) restores the capacity to produce IL-4 in cells primed under Th2 conditions in the absence of IL-2, suggesting that STAT5 activation plays a critical role in Th2 differentiation (32-Zhu-2003,33-Zhu-2004). Additionally, IL-2 critically regulate TH2 differentiation in a STAT5-dependent manner, acting early at the locus encoding the IL-4Ra to induce expression of this receptor (IL-4Rα)  (34-Liao-2008) and later to open chromatin accessibility at the TH2 locus, which encodes IL-4, IL-13 (62-Cote-Sierra-2004).

The development of Th2 cells was impaired in STAT5a-/-CD4+ T cells even in the presence of IL-4 and that the retrovirus-mediated expression of STAT5a restored Th2 cell differentiation in STAT5a-/-CD4+ T cells. Th2 cell–mediated immune responses are diminished in STAT5a-/- mice. When stimulated with anti-CD3 mAb, CD4+ T cells that produced IL-4 but not IFN-γ (Th2 cells) were significantly decreased in STAT5a-/- mice as compared with those in wild-type mice, suggesting that STAT5a plays a regulatory role in T helper cell differentiation  (63-Kagami-2001).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

IL-2 stabilizes the accessibility of the Il4 gene, and STAT5, a key transducer of IL-2 function, binds to sites in the second intron of the Il4 gene (62-Cote-Sierra-2004).

5C.C7 cells infected with a retrovirus expressing a constitutively active form of STAT5A (STAT5A1*6) were primed for IL-4 production.

STAT5a/b mutant peripheral T cells in mice are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression. The STAT5 proteins are essential mediators of IL-2 signaling in T cells (31-Willerford-1995).

IL-2 is one of the earliest cytokines produced by activated T cells and mediates its actions primarily through the activation of STAT5 proteins. A STAT5-chromatin immunoprecipitation assay (ChIP) was performed using chromatin from freshly isolated CD4 T cells to identify in vivo IL-2-activated STAT5 gene targets. The immunoprecipitated chromatin yielded a number of distinct clones based on sequencing. One clone mapped to chromosome 16 at −152,916 to −153,096 upstream of the C-MAF gene, and contained a consensus interferon gamma activated sequence (GAS) motif (90-Rani-2011).

Heat map of expression profiles of IL-2–regulated genes (sorted by superenhancer binding scores for STAT5, from strongest to weakest) reveals STAT5-bound superenhancer-containing genes were highly induced by IL-2 (91-Li-2018).

Cells primed under Th2 but not Th1 conditions show association of STAT5A with HSII and HSIII. We have also shown that cells infected with the STAT5A1*6 retrovirus acquire IL-4-producing capacity and that STAT5 is associated with DNA elements near HSII and HSIII (32-Zhu-2003).

CD4+ T cell–mediated allergic inflammation is diminished in STAT5a-deficient (STAT5a-/-) mice. Further, Th2 cell differentiation was also impaired in STAT5a-/- mice even when purified CD4+ T cells were stimulated with anti-CD3 plus anti-CD28 antibodies in the presence of interleukin-4 (63-Kagami-2001).

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

Th2 cell differentiation from antigen-stimulated splenocytes was significantly decreased in STAT5a-/- mice as compared with that in wild-type mice. Intrinsic expression of STAT5a in CD4+ T cells is required for Th2 cell differentiation and that STAT5a is involved in the development of CD4+CD25+ immunoregulatory T cells that modulate T helper cell differentiation toward Th2 cells (63-Kagami-2001).

IL-4 production was induced by STAT5 phosphorylation. STAT5 phosphorylation facilitates STAT5 dimerization, transport to the nucleus and gene regulation (56-Levy-2002). STAT5 is able to inhibit PPAR-regulated gene transcription and conversely, ligand-activated PPAR able to inhibit STAT5-regulated transcription. PPARs (peroxisome proliferator activated receptors) are members of the nuclear hormone receptor superfamily. STAT5 and PPAR disparate pathways are subject to mutually inhibitory crosstalk. The extent of the inhibitory crosstalk was dependent on the relative levels of expression of each transcription factor (92-Shipley-2004).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

At present, no evidence is found.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

Once STATs are recruited to the activated JAK/receptor complex and tyrosine-phosphorylated within the SH2 domain by JAKs, they form dimers and/or tetramers, translocate to the nucleus, and associate with promoter regions such as Gamma Activated Sequence (GAS) elements. STAT dimers can bind to gamma interferon–activated sequence (GAS) DNA sequences (TTCN3GAA) to induce transcription. The STAT5 dimers can also form tetramers through interactions between residues (I28, F81, and L82) in their N-terminal regions. These STAT5 tetramers bind to pairs of GAS motifs separated by a linker of 6–22 nucleotides (100-Lin-2012). Mutational studies demonstrate that STAT5 is important for IL-2-induced gene expression. The interaction of STATs with gene promoters can enhance the expression of its target genes (101-Able-2017).

While the wild-type construct showed 4.6-fold IL-2 inducibility in YT cells, selective mutation of the GAScI (M1), GASn (M2), and GAScII (M3) motifs modestly lowered IL-2 inducibility (M1 1.7-fold, M2 2.9-fold, M3 1.6-fold, respectively). Double mutation of GAScI and GASn (M4) or of GASn and GAScII (M5) more potently decreased IL-2 inducibility, and simultaneous mutation of GAScI and GAScII (M6) or of all the GAS motifs (M7) abrogated IL-2 inducibility (M4 1.2-fold, M5 1.4-fold, M6 1.0-fold, M7 1.0-fold, respectively)). These results suggest that all of the GAS motifs are required for maximal IL-2 inducibility including IL-4 induction(79-Kim-2001).

This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

A STAT5 binding site (TTCATGGAA) has been identified in intron 2 of the Il4 gene. Hypersensitivity site (HS) V (also known as CNS2), a 3’ enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in Th2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. HS V-deficient (ΔV) mice were the complete abrogation of IgE production despite only mild reduction in Th2 responses. HS V-deficiency affected Il4 transcription in T cells. Naive T cells lacking the HS V (CNS2) region were completely unable to produce Il4 transcripts following ex-vivo stimulated with anti-CD3 and anti-CD28 antibodies for 180 min. In a similar time course assay (240 min), in vitro differentiated Th2 cells stimulated with PMA and ionomycin showed only a 50% reduction in Il4 transcription (102-Vijayanand-2012).

Phosphorylation of STAT5 was found to be decreased nearly two-fold in NOX2-deficient T cells as compared to wild type controls by intracellular staining at 12 and 24 hours after activation with immobilized anti-CD3 and soluble anti-CD28. PCR analysis also found decreases in Il4 and Il4rα mRNA expression in NOX2-deficient T cells (97-Shatynski-2012).

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

Adenosine inhibited IL-2-dependent proliferation of the CTLL-2 T cell line. The adenosine inhibitory effect was associated with a reduction in tyrosine phosphorylation of STAT5a and STAT5b that was mediated by the activation of a protein tyrosine phosphatase (PTP). The PTP Src homology region 2 domain-containing phosphatase-2 (SHP-2) was implicated in STAT5a/b dephosphorylation because adenosine strongly increased tyrosine phosphorylation of SHP-2 and the formation of complexes consisting of SHP-2 and STAT5 in IL-2- stimulated CTLL-2 T cells. In contrast, adenosine did not affect the phosphorylation status of the upstream kinases Jak1 or Jak3. The inhibitory effect of adenosine on STAT5a/b phosphorylation was mediated through cell surface A2a and A2b receptors and involved associated cAMP/protein kinase A (PKA)-dependent signaling pathways (78-Zhang-2004).

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

STAT5 has been shown to up-regulate a number of molecules, including cytokine-inducible SH2 proteins (CIS family, also referred to as the SOCS or SSI family) (103-Yasukawa-2000). Some CIS family proteins might be involved in the cross-regulation of cytokine network and may regulate Th1 cell and Th2 cell differentiation (104-Losman-1999,105-Dickensheets-1999). CIS1, a prototype of CIS family proteins, is induced by STAT5 and inhibits STAT5 activation by blocking the interaction between STAT5 and cytokine receptors (103-Yasukawa-2000). Thus, CIS1 seems to function in a classical negative feedback of STAT5 signaling.

IL-2 acts either on the same cell that secretes the cytokine, for instance, IL-2 produced by T cells operates on the same T cells that made it or on a nearby cell. With highest levels in secondary lymphoid organs, IL-2 is believed to act in an autocrine or paracrine manner to support effector and memory CD8 T cell differentiation (88-Kalia-2018). IL-2Rα expression is triggered by antigen, mitogen lectins, or antibodies to the TCR through STAT5. These signals also result in secretion of IL-2, which in turn can increase and prolong IL-2Rα expression, thus acting as a positive feedback regulator of its own high-affinity receptor (106-Waldmann-1989). Therefore, STAT5 deficiency induced disrupted T cell functions

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help



List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

31.      Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W. (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530

32.      Zhu, J., Cote-Sierra, J., Guo, L., and Paul, W. E. (2003) Stat5 activation plays a critical role in Th2 differentiation. Immunity 19, 739-748

33.      Zhu, J., Min, B., Hu-Li, J., Watson, C. J., Grinberg, A., Wang, Q., Killeen, N., Urban, J. F., Jr., Guo, L., and Paul, W. E. (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nature immunology 5, 1157-1165

34.      Liao, W., Schones, D. E., Oh, J., Cui, Y., Cui, K., Roh, T. Y., Zhao, K., and Leonard, W. J. (2008) Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nature immunology 9, 1288-1296

62.      Cote-Sierra, J., Foucras, G., Guo, L., Chiodetti, L., Young, H. A., Hu-Li, J., Zhu, J., and Paul, W. E. (2004) Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci U S A 101, 3880-3885

63.      Kagami, S., Nakajima, H., Suto, A., Hirose, K., Suzuki, K., Morita, S., Kato, I., Saito, Y., Kitamura, T., and Iwamoto, I. (2001) Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood 97, 2358-2365

78.      Zhang, H., Conrad, D. M., Butler, J. J., Zhao, C., Blay, J., and Hoskin, D. W. (2004) Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. J Immunol 173, 932-944

79.      Kim, H. P., Kelly, J., and Leonard, W. J. (2001) The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15, 159-172

88.      Kalia, V., and Sarkar, S. (2018) Regulation of Effector and Memory CD8 T Cell Differentiation by IL-2-A Balancing Act. Front Immunol 9, 2987

89.      Hural, J. A., Kwan, M., Henkel, G., Hock, M. B., and Brown, M. A. (2000) An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. J Immunol 165, 3239-3249

90.      Rani, A., Afzali, B., Kelly, A., Tewolde-Berhan, L., Hackett, M., Kanhere, A. S., Pedroza-Pacheco, I., Bowen, H., Jurcevic, S., Jenner, R. G., Cousins, D. J., Ragheb, J. A., Lavender, P., and John, S. (2011) IL-2 regulates expression of C-MAF in human CD4 T cells. J Immunol 187, 3721-3729

91.      Li, Y., Liu, X., Wang, W., Wang, S., Zhang, J., Jiang, S., Wang, Y., Li, L., Li, J., Zhang, Y., and Huang, H. (2018) Low-dose IL-2 expands CD4(+) regulatory T cells with a suppressive function in vitro via the STAT5-dependent pathway in patients with chronic kidney diseases. Renal failure 40, 280-288

92.      Shipley, J. M., and Waxman, D. J. (2004) Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b. Toxicology and applied pharmacology 199, 275-284

93.      Fang, X., Zhang, L., Feng, Y., Zhao, Y., and Dai, J. (2008) Immunotoxic effects of perfluorononanoic acid on BALB/c mice. Toxicological sciences : an official journal of the Society of Toxicology 105, 312-321

94.      Adamson, A. S., Collins, K., Laurence, A., and O'Shea, J. J. (2009) The Current STATus of lymphocyte signaling: new roles for old players. Current opinion in immunology 21, 161-166

95.      Ben-Sasson, S. Z., Le Gros, G., Conrad, D. H., Finkelman, F. D., and Paul, W. E. (1990) IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production. J Immunol 145, 1127-1136

96.      McDyer, J. F., Li, Z., John, S., Yu, X., Wu, C. Y., and Ragheb, J. A. (2002) IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production. J Immunol 169, 2736-2746

97.      Shatynski, K. E., Chen, H., Kwon, J., and Williams, M. S. (2012) Decreased STAT5 phosphorylation and GATA-3 expression in NOX2-deficient T cells: role in T helper development. European journal of immunology 42, 3202-3211

98.      He, X., Smeets, R. L., Koenen, H. J., Vink, P. M., Wagenaars, J., Boots, A. M., and Joosten, I. (2011) Mycophenolic acid-mediated suppression of human CD4+ T cells: more than mere guanine nucleotide deprivation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 11, 439-449

99.      Liu, Y., Yang, T., Li, H., Li, M. H., Liu, J., Wang, Y. T., Yang, S. X., Zheng, J., Luo, X. Y., Lai, Y., Yang, P., Li, L. M., and Zou, Q. (2013) BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway. British journal of pharmacology 168, 632-643

100.    Lin, J. X., Li, P., Liu, D., Jin, H. T., He, J., Ata Ur Rasheed, M., Rochman, Y., Wang, L., Cui, K., Liu, C., Kelsall, B. L., Ahmed, R., and Leonard, W. J. (2012) Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 36, 586-599

101.    Able, A. A., Burrell, J. A., and Stephens, J. M. (2017) STAT5-Interacting Proteins: A Synopsis of Proteins that Regulate STAT5 Activity. Biology 6

102.    Vijayanand, P., Seumois, G., Simpson, L. J., Abdul-Wajid, S., Baumjohann, D., Panduro, M., Huang, X., Interlandi, J., Djuretic, I. M., Brown, D. R., Sharpe, A. H., Rao, A., and Ansel, K. M. (2012) Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity 36, 175-187

103.    Yasukawa, H., Sasaki, A., and Yoshimura, A. (2000) Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18, 143-164

104.    Losman, J. A., Chen, X. P., Hilton, D., and Rothman, P. (1999) Cutting edge: SOCS-1 is a potent inhibitor of IL-4 signal transduction. J Immunol 162, 3770-3774

105.    Dickensheets, H. L., Venkataraman, C., Schindler, U., and Donnelly, R. P. (1999) Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Proc Natl Acad Sci U S A 96, 10800-10805

106.    Waldmann, T. A. (1989) The multi-subunit interleukin-2 receptor. Annual review of biochemistry 58, 875-911