Transcriptional regulation of murine IL-33 by TLR and non-TLR agonists.
IL-33, a member of the IL-1 family of cytokines, is produced by many cell types, including macrophages, yet its regulation is largely unknown. Treatment of primary murine macrophages with a panel of TLR (e.g., TLR2, TLR3, TLR4, and TLR9) agonists and non-TLR (e.g., MDA5, RIG-I) agonists revealed a pattern of gene and protein expression consistent with a role for IFN regulatory factor-3 (IRF-3) in the expression of IL-33. Accordingly, induction of IL-33 mRNA was attenuated in IRF-3(-/-) macrophages and TBK-1(-/-) mouse embryonic fibroblasts. Despite the fact that all IL-33 agonists were IRF-3 dependent, LPS-induced IL-33 mRNA was fully inducible in IFN-β(-/-) macrophages, indicating that IL-33 is not dependent on IFN-β as an intermediate. Epinephrine and Bordetella pertussis adenylate cyclase toxin (ACT), cAMP-activating agents, activate CREB and greatly synergize with LPS to induce IL-33 mRNA in macrophages. Both LPS-induced and ACT/LPS-enhanced expression of IL-33 mRNA was partially, but significantly, inhibited by the protein kinase A inhibitor H-89 but not by tyrosine kinase or protein kinase C inhibitors. Two IL-33 mRNA species derived from two alternative promoters encode full-length IL-33; however, the shorter "A" species is preferentially induced by all IL-33-inducing agonists except Newcastle disease virus, a RIG-I agonist that induced expression of both "A" and "B" transcripts. Together, these studies greatly extend what is currently known about the regulation of IL-33 induction in macrophages stimulated by bacterial and viral agonists that engage distinct innate immune signaling pathways.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Swamy Kumar
SK
Polumuri
Gift Gunaraj
GG
Jayakar
Kari Ann
KA
Shirey
Zachary J
ZJ
Roberts
Darren J
DJ
Perkins
Paula M
PM
Pitha
Stefanie N
SN
Vogel
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000382:microbiology / Q000821:virology; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology*
C506535:Il33 protein, mouse; D050838:Interferon Regulatory Factor-3; D000067596:Interleukin-33; D007378:Interleukins; C494233:Irf3 protein, mouse; D008024:Ligands; D012333:RNA, Messenger; D051193:Toll-Like Receptors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases