The regulation of Th1 responses by the p38 MAPK.

Abstract

IL-12 is a dimeric cytokine that is produced primarily by APCs. In this study we examined the role that the p38 MAPKs (MAPK/p38) play in regulating IL-12 production. We show that inhibition of p38 dramatically increased IL-12 production upon stimulation, while decreasing TNF-α. This reciprocal effect on these two cytokines following MAPK/p38 inhibition occurred in many different APCs, following a variety of different stimuli. IL-12 production was also increased in macrophages treated with small interfering RNA to limit p38α expression, and in macrophages deficient in MKK3, a kinase upstream of p38. The increase in IL-12 production following MAPK/p38 inhibition appears to be due to enhanced IL-12 (p40) mRNA stability. We show that MAPK/p38 inhibition can promote Th1 immune responses and thereby enhance vaccine efficacy against leishmaniasis. In a mouse model of Leishmania major infection, vaccination with heat-killed L. major plus CpG and SB203580 elicited complete protection against infection compared with heat-killed L. major plus CpG without SB203580. Thus, this work suggests that MAPK/p38 inhibitors may be applied as adjuvants to bias immune responses and improve vaccinations against intracellular pathogens.

• Authors: Ziyan Yang, Xia Zhang, Patricia A Darrah, David M Mosser
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 10 Pg. 6205-13 (Nov 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20937847 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Leishmaniasis Vaccines
• Pyridines
• RNA, Small Interfering
• Tumor Necrosis Factor-alpha
• Interleukin-12
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Animals
• Antigen-Presenting Cells (immunology, metabolism)
• Blotting, Western
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (immunology)
• Imidazoles (pharmacology)
• Interleukin-12 (biosynthesis, immunology)
• Leishmaniasis (immunology, prevention & control)
• Leishmaniasis Vaccines (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Pyridines (pharmacology)
• RNA, Small Interfering
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection
• Tumor Necrosis Factor-alpha (biosynthesis, immunology)
• p38 Mitogen-Activated Protein Kinases (immunology, metabolism)