TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation.
During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells.
Vanden Bush
Tony J
TJ
Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USA.
Bishop
Gail A
GA
D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism* / Q000502:physiology
D019013:CD40 Antigens; D016207:Cytokines; D015850:Interleukin-6; D008562:Membrane Glycoproteins; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases