Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice

The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-t erminal kinase (JNK) MAPK pathway, is activated in response to cellular str ess and inflammation and is involved in many fundamental biological process es. To study the role of the p38 MAPK pathway in vivo, we have used homolog ous recombination in mice to inactivate the Mkk3 gene, one of the two speci fic MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viabl e and fertile however, they were defective in interleukin-12 (IL-12) produc tion by macrophages and dendritic cells, Interferon-gamma production follow ing immunization with protein antigens and in vitro differentiation of naiv e T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at lea st partly transcriptional, since inhibition of this pathway blocks IL-12 p4 0 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated thro ugh MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells.