Production of IFN-α by human and murine mast cells induced by double-stranded RNA: Evidence for activation through toll-like receptor-3 (TLR-3)

Abstract

Rationale Type I IFNs are critical for host defense against viruses, but the source of these cytokines are not fully understood. While plasmacytoid dendritic cells are primary producers in some viral infections, they do not contribute in all cases. Given that mast cells (MC) are located at epithelial surfaces where initial exposure to invading viruses may occur, we explored the ability of MC to produce type I IFNs following exposure to viruses, and polyI:C, a synthetic mimic of viral dsRNA. Methods and results Respiratory syncytial virus (RSV), type-1 reovirus, influenza virus (PR8), and polyI:C induced IFN-α production from human peripheral blood cultured MC (HCMC). PolyI:C also induced IFN-α and IFN-β expression by two MC lines, LAD and HMC-1. PolyI:C did not induce TNF, IL-1β, or IL-5 expression, as did other toll-like receptor (TLR) ligands (LPS, PGN or CpGs). PolyI:C-induced IFN-α production was partially dependent on NF-κB, p38 and JNK MAP kinase signaling pathways. RT-PCR and Western blot analysis confirmed expression of TLR-3 by all MC. HCMC also expressed TLR-1, -2, -4, -5, -6, -7 and -8. Antibodies to TLR-3 but not to TLR-2 or TLR-4 blocked polyI:C-induced IFN-α production and bone-marrow derived MC from TLR-3 knock-out mice showed an ablated response to polyI:C. Conclusions Murine and human MC produce type I IFNs following exposure to viruses and dsRNA, the latter via specific interactions with TLR-3. These data suggest that MC contribute to innate immune responses to viral infection, as well as to the induction of adaptive immunity via the production of type I IFNs.