A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation

• Published in: The Journal of clinical investigation Vol. 114; no. 6; pp. 857 - 866
• Main Authors: Sugimoto, Kenji, Ohata, Mutsuhiro, Miyoshi, Jun, Ishizaki, Hiroyoshi, Tsuboi, Naotake, Masuda, Akio, Yoshikai, Yasunobu, Takamoto, Masaya, Sugane, Kazuo, Matsuo, Seiichi, Shimada, Yasuhiro, Matsuguchi, Tetsuya
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 15.09.2004
• ISSN: 0021-9738
• DOI: 10.1172/JCI200420014

A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal–regulated kinase (ERK) activation and production of TNF-α and PGE 2 in LPS-stimulated macrophages. We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or synthetic lipopeptide, activated ERK in a Cot/Tpl2–independent manner. Peritoneal macrophages and bone marrow–derived DCs from Cot/Tpl2 –/– mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice. Enhanced IL-12 production in Cot/Tpl2 –/– macrophages is, at least partly, regulated at the transcriptional level, and the elevated IL-12 mRNA level in Cot/Tpl2 –/– macrophages is accompanied by decreased amounts of IL-12 repressors, such as c-musculoaponeurotic fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter–binding protein (GA-12–binding protein; GAP-12) in the nucleus. Consistently, Cot/Tpl2 –/– mice showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA–guided vaccination.