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Nagaraj Gowda, Jessie Fang, Nicola Heller, Regulation of IL-4-induced insulin receptor substrate-2 activation in allergic inflammation (P6294), The Journal of Immunology, Volume 190, Issue Supplement_1, May 2013, Page 184.8, https://doi.org/10.4049/jimmunol.190.Supp.184.8
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Abstract
Allergic asthma is a chronic airway disease driven by Th2 cytokines, IL-4, -5 and -13. IL-4 receptors activate IRS-2/STAT6 signaling to induce differentiation of M2 macrophages, cells associated with allergic lung inflammation in mice and humans. IL-4, but not IL-13, strongly induced tyrosine phosphorylation (pY) of IRS-2 and M2 gene expression. Understanding regulation of IRS-2 activation is essential for designing novel therapeutics. We hypothesized that both induction of SOCS proteins and serine phosphorylation (pS) of IRS-2 downregulates IRS-2 signaling. To test this, we stimulated both human monocytes (U937 cells) and mouse primary macrophages with IL-4 and observed robust pY-IRS2 that peaked at 60 min and returned to baseline by 150 min. Kinetics of induction of mRNA for SOCS1, SOCS3 and CIS by IL-4 matched the decrease in pY-IRS-2. Using a siRNA knockdown approach, we found that SOCS1 is responsible for downregulating pY-IRS2 but not CIS and SOCS3. SOCS proteins bind to ubiquitin ligase complexes and target proteins for proteasomal degradation. Proteasome inhibitor-treated, IL-4-stimulated U937 cells showed extended pY-IRS2 signaling. In U937 cells, IL-4-induced pS-IRS-2 had an opposite pattern to pY-IRS-2 and when serine phosphatases were inhibited, pY-IRS-2 dramatically decreased. Using serine kinase inhibitors, we found that inhibition of mTORC1 prolonged pY-IRS-2 signaling in BMM and U937 cells, thus uncovering novel, targetable regulators of allergic inflammation.
