Cot/Tpl2 regulates IL-23 p19 expression in LPS-stimulated macrophages through ERK activation.
We have previously reported that a serine/threonine protein kinase, Cot/Tpl2, is a negative regulator of 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 in LPS-stimulated wild-type macrophages. As Cot/Tpl2 is an essential upstream component of the ERK 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.
Kakimoto
K
K
Department of Oral Biochemistry, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Musikacharoen
T
T
Chiba
N
N
Bandow
K
K
Ohnishi
T
T
Matsuguchi
T
T
D000818:Animals; D002454:Cell Differentiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*
D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D018664:Interleukin-12; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
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