Background Interleukin (IL)-32 is known to exert adujvant effects on innate immune response and has an important role in inflammatory disease, such as rheumatoid arthritis . However, receptors and downstream signaling pathways remain to be clarified, except for a role of proteinase 3 (PR3)-binding protein . Although it was also speculated that protease activated receptor-2 (PAR2) mediated the activity of IL-32 through PR3 , there is a paucity of reports dealing with the relationship between IL-32 and PAR2.
Objectives We have investigated about the potential signaling pathway of IL-32-TNFα or type I interferon axis was analyzed in vitro.
Methods Using THP-1 cells, in vitro effect of exogenous IL-32γ on TNFα or IFN-β, one of the type I interferon, production was assessed with or without PMSF, inhibitor for serine proteases. And it was also assessed with or without siRNA against PR3 or PAR2. In another experiments, siRNA against TIR-domain-containing adapter-inducing interferon-beta (TRIF), downstream signaling of PAR2 , or TRIF-related adaptor molecule (TRAM), which was the molecule recruited by TLR4 to bind TRIF , was administered to THP-1 with IL-32γ and TNFα or IFN-β production was assessed.
Results In human monocyte cell line, THP-1 cells, exogenous IL-32γ alone was capable of stimulating TNFα and IFN-β production, which was markedly diminished by either addition of PMSF or siRNA against PR3 or PAR2. Furthermore, siRNA against TRIF, but not TRAM, also hampered IL-32γ-induced TNFα or IFN-β production. Collectively, IL-32-PR3 interaction may be profoundly bound to PAR2-TRIF axis, not TLR4-TRAM-TRIF axis, followed by robust TNFα and IFN-β production, since PAR2 reportedly sensed serine proteases such as PR3.
Conclusions IL-32 induces TNFα and type I interferon via PR3-PAR2-TRIF axis and may play an important role in inflammatory disease.
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Disclosure of Interest None Declared
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