title: Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling.
abstract: Interferon-gamma and interleukin-4 (IL-4) induce distinct gene expression profiles in macrophages by differentially activating signal transducers and activators of transcription (STAT)1 and STAT6, respectively. The role of suppressor of cytokine signaling (SOCS)-1 as a negative regulator of IFN-gamma signaling is well established. However, its potential role as a negative regulator of IL-4 signaling has not been explored. We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent, whereas induction of SOCS-1 by IFN-gamma is STAT1-dependent. Unlike their common ability to induce expression of SOCS-1, IL-4 also induced expression of SOCS-2 but not SOCS-3 in macrophages, whereas IFN-gamma induced expression of SOCS-3 but not SOCS-2. Forced expression of SOCS-1 or SOCS-3, but not SOCS-2, inhibited activation of STAT6 by IL-4. Moreover, SOCS-1 appears to serve as an endogenous regulator of IL-4 signaling in macrophages because the magnitude and duration of STAT6 activation as well as IL-4-mediated gene expression were much greater in SOCS-1-deficient (SOCS-1(-/-)) macrophages than in wild-type macrophages. Our findings demonstrate that, like IFN-gamma, IL-4 also induces expression of SOCS-1 in macrophages, and SOCS-1 feedback inhibits expression of STAT6-responsive genes.
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dickensheets
authors.forename: N
authors.initials: N
authors.lastname: Vazquez
authors.forename: F
authors.initials: F
authors.lastname: Sheikh
authors.forename: S
authors.initials: S
authors.lastname: Gingras
authors.forename: P J
authors.initials: PJ
authors.lastname: Murray
authors.forename: J J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: R P
authors.initials: RP
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D015536:Down-Regulation; D025461:Feedback, Physiological; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C108944:SOCS1 protein, human; D050800:STAT6 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015847:Interleukin-4