Stress signaling boosts interferon-induced gene transcription in macrophages

Promoters of antimicrobial genes function as logic boards, integrating signals of innate immune responses. One such set of genes is stimulated by interferon (IFN) signaling, and the expression of these genes [IFN-stimulated genes (ISGs)] can be further modulated by cell stress–induced pathways. Here, we investigated the global effect of stress-induced p38 mitogen-activated protein kinase (MAPK) signaling on the response of macrophages to IFN. In response to cell stress that coincided with IFN exposure, the p38 MAPK-activated transcription factors CREB and c-Jun, in addition to the IFN-activated STAT family of transcription factors, bound to ISGs. In addition, p38 MAPK signaling induced activating histone modifications at the loci of ISGs and stimulated nuclear translocation of the CREB coactivator CRTC3. These actions synergistically enhanced ISG expression. Disrupting this synergy with p38 MAPK inhibitors improved the viability of macrophages infected with Listeria monocytogenes. Our findings uncover a mechanism of transcriptional synergism and highlight the biological consequences of coincident stress-induced p38 MAPK and IFN-stimulated signal transduction. Description Stress-induced p38 activity enhances the positive and negative effects of macrophage interferon responses. Stressed into boosting interferon signaling Interferon signaling stimulates the innate immune response to infection and is regulated in part by stress signaling mediated by the kinase p38. Boccuni et al. clarified the functional interaction between these pathways and the consequences of their integration. In macrophages stimulated with interferon, coincident stress signaling induced a p38-dependent recruitment of additional factors to interferon-stimulated genes, synergistically enhancing their expression. In Listeria-infected cultured macrophages, this boost elicited greater production of pathogen-fighting factors like cytokines and nitric oxide, but it also increased cell death. Blocking p38 signaling preserved macrophage viability without sacrificing function. The findings indicate that p38 signaling enhances not only the beneficial effects, but also the detrimental effects of interferon-mediated immune responses.-LKF