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-?B, 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.
Department of Oral Biochemistry, Field of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
Kenjiro
K
Bandow
Joji
J
Kusuyama
Mitsuo
M
Shamoto
Kyoko
K
Kakimoto
Tomokazu
T
Ohnishi
Tetsuya
T
Matsuguchi
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism*; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*
D018925:Chemokines; D017931:DNA Primers; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D048049:Extracellular Signal-Regulated MAP Kinases