Cot/Tpl2 regulates IL-23 p19 expression in LPS-stimulated macrophages through ERK activation

RESUMEN

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ABSTRACT

We have previously reported that a serine/threonine protein kinase, Cot/Tpl2, is a negative regulatorof Th1-type immunity through inhibiting IL-12 expression in antigen presenting cells (APCs)stimulated by Toll-like receptor (TLR) ligands. We here show that Cot/Tpl2-/- macrophages produce significantly less IL-23, an important regulator of Th17-type response, than the wild-type counterparts in response to lipopolysaccharide (LPS), which is a ligand for TLR4. The decreased IL-23 production in Cot/Tpl2-/- macrophages is, at least partly, regulated at the transcriptional level, as the LPS-mediated IL-23 p19 mRNA induction was significantly less in Cot/Tpl2-/- macrophages. Chemical inhibition of extracellular signal-regulated kinase (ERK) activity similarly inhibited IL-23 expression inLPS-stimulated wild-type macrophages. As Cot/Tpl2 is an essential upstream component of theERK activation pathway of LPS, it is suggested that Cot/Tpl2 positively regulates IL-23 expression through ERK activation. These results indicate that Cot/Tpl2 may be involved in balancing Th1/Th17 differentiation by regulating the expression ratio of IL-12 and IL-23 in APCs (AU)