LPS-induced chemokine expression in both MyD88-dependent and -independent manners is regulated by Cot/Tpl2-ERK axis in macrophages

LPS signaling is mediated through MyD88-dependent and -independent pathways, activating NF-κB, MAP kinases and IRF3. Cot/Tpl2 is an essential upstream kinase in LPS-mediated activation of ERKs. Here we explore the roles of MyD88 and Cot/Tpl2 in LPS-induced chemokine expression by studying myd88−/− and cot/tpl2−/− macrophages. Among the nine LPS-responsive chemokines examined, mRNA induction of ccl5, cxcl10, and cxcl13 is mediated through the MyD88-independent pathway. Notably, Cot/Tpl2-ERK signaling axis exerts negative effects on the expression of these three chemokines. In contrast, LPS-induced gene expression of ccl2, ccl7, cxcl2, cxcl3, ccl8, and cxcl9 is mediated in the MyD88-dependent manner. The Cot/Tpl2-ERK axis promotes the expression of the first four and inhibits the expression of the latter two. Thus, LPS induces expression of multiple chemokines through various signaling pathways in macrophages.

► LPS induces cxcl10, 13, and ccl5 expressions through the MyD88-independent pathway.
► MyD88 is required for the LPS-induced expression of ccl2, 7, 8, cxcl2, 3, and 9.
► Cot/Tpl2-ERK axis is inhibitory to the LPS-induced expression of ccl8 and cxcl9.
► LPS induces multiple chemokine expressions through various pathways in macrophages.