title: IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis.
abstract: Interleukin (IL)-32 is known to exert adujvant effects on innate immune response, however, receptors and downstream signaling pathways remain to be clarified. Here we found that IL-32γ upregulated serine protease activity of proteinase-3 (PR3), in turn triggering protease-activated receptor 2 (PAR2) signaling. Interestingly, silencing of PR3 or PAR2 using siRNA markedly diminished IL-32γ-induced TNFα and IFN-β mRNA expression. IL-32γ-PAR2 axis utilized TRIF and Ras-Raf-1 pathways. On stimulation with lipopolysaccharide (LPS), differential activation of protein kinase C isoforms modulated the balance between LPS-TLR4-TRIF and IL-32-PAR2-TRIF axes, because LPS was a strong inducer of IL-32γ. IL-32-PAR2-TRIF axis might serve not only as an extracellular sensor of bacterial and autologous proteases, but also as a modulator of innate and adaptive immunity during infection.
authors.affiliation: Department of Orthopaedic Surgery, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakayama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Niki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takeda
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ikegami
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008954:Models, Biological; D011493:Protein Kinase C / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C496971:IL32 protein, human; D007378:Interleukins; D008070:Lipopolysaccharides; D044464:Receptor, PAR-2; C470409:TICAM1 protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras)