Inhibition of p38 MAP kinase during cellular activation results in IFN-gamma-dependent augmentation of IL-12 production by human monocytes/macrophages

Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antig en-presenting cells that promotes cellular immunity and enables the generat ion of protective immunity against intracellular pathogens and tumours. The refore, modulation of IL-12 activity is a primary immunotherapeutic goal. H owever, little is known about its regulation. Signalling via p38 MAPK has b een implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK in hibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS in duced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-indepe ndent and T cell-dependent stimuli but not in unstimulated cultures, indica ting that activation signals are required. Furthermore, the production of I FN-gamma by T cells is crucial as production was not increased in LPS-stimu lated, purified adherent monocytes/macrophages without the addition of exog enous IFN-gamma. These results provide evidence that p38 MAPK has an unexpe cted suppressive effect on IL-12p40 gene transcription, and suggests interp lay between p38 MAPK- and IFN-gamma -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of I L-12 as a key immunoregulatory cytokine suggests that the clinical applicat ion of pyrinidyl imidazole inhibitors, such as SB203580, may need to be rea ssessed.