title: Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome.
abstract: Allergic asthma is a chronic lung disease initiated and driven by Th2 cytokines IL-4/-13. In macrophages, IL-4/-13 bind IL-4 receptors, which signal through insulin receptor substrate (IRS)-2, inducing M2 macrophage differentiation. M2 macrophages correlate with disease severity and poor lung function, although the mechanisms that regulate M2 polarization are not understood. Following IL-4 exposure, suppressor of cytokine signaling (SOCS)1 is highly induced in human monocytes. We found that siRNA knockdown of SOCS1 prolonged IRS-2 tyrosine phosphorylation and enhanced M2 differentiation, although siRNA knockdown of SOCS3 did not affect either. By co-immunoprecipitation, we found that SOCS1 complexes with IRS-2 at baseline, and this association increased after IL-4 stimulation. Because SOCS1 is an E3 ubiquitin ligase, we examined the effect of proteasome inhibitors on IL-4-induced IRS-2 phosphorylation. Proteasomal inhibition prolonged IRS-2 tyrosine phosphorylation, increased ubiquitination of IRS-2, and enhanced M2 gene expression. siRNA knockdown of SOCS1 inhibited ubiquitin accumulation on IRS-2, although siRNA knockdown of SOCS3 had no effect on ubiquitination of IRS-2. Monocytes from healthy and allergic individuals revealed that SOCS1 is induced by IL-4 in healthy monocytes but not allergic cells, whereas SOCS3 is highly induced in allergic monocytes. Healthy monocytes displayed greater ubiquitination of IRS-2 and lower M2 polarization than allergic monocytes in response to IL-4 stimulation. Here, we identify SOCS1 as a key negative regulator of IL-4-induced IRS-2 signaling and M2 differentiation. Our findings provide novel insight into how dysregulated expression of SOCS increases IL-4 responses in allergic monocytes, and this may represent a new therapeutic avenue for managing allergic disease.
authors: From the Department of Anesthesiology and Critical Care Medicine and.
authors: Sarah M
authors: SM
authors: McCormick
authors: From the Department of Anesthesiology and Critical Care Medicine and.
authors: Nagaraj
authors: N
authors: Gowda
authors: From the Department of Anesthesiology and Critical Care Medicine and.
authors: Jessie X
authors: JX
authors: Fang
authors: From the Department of Anesthesiology and Critical Care Medicine and Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 nheller@jhmi.edu.
authors: Nicola M
authors: NM
authors: Heller
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: C508598:IL4 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D025801:Ubiquitin; D015847:Interleukin-4; D014443:Tyrosine; D046988:Proteasome Endopeptidase Complex
keywords: allergy; asthma; insulin receptor substrate 2; interleukin-4; macrophage; monocyte; phosphotyrosine signaling; signal transduction; suppressor of cytokine signaling 1; ubiquination