14-3-3? and 14-3-3? inhibit Toll-like receptor (TLR)-mediated proinflammatory cytokine induction.

ABSTRACT: Toll-like receptors (TLRs) are a group of pattern recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Limited studies have applied proteomics toward understanding the dynamics of TLR signaling. Herein, a proteomics approach identified 14-3-3? and 14-3-3? proteins as new members of the TLR signaling complex. Toward the functional characterization of 14-3-3? and 14-3-3? in TLR signaling, we have shown that both of these proteins impair TLR2, TLR3, TLR4, TLR7/8, and TLR9 ligand-induced IL-6, TNF?, and IFN-? production. We also show that 14-3-3? and 14-3-3? impair TLR2-, TLR3-, TLR4-, TLR7/8-, and TLR9-mediated NF-?B and IFN-? reporter gene activity. Interestingly, although the 14-3-3 proteins inhibit poly(I:C)-mediated RANTES production, 14-3-3 proteins augment Pam(3)CSK(4), LPS, R848, and CpG-mediated production of RANTES (regulated on activation normal T cell expressed and secreted) in a Mal (MyD88 adaptor-like)/MyD88-dependent manner. 14-3-3? and 14-3-3? also bind to the TLR adaptors and to both TRAF3 and TRAF6. Our study conclusively shows that 14-3-3? and 14-3-3? play a major regulatory role in balancing the host inflammatory response to viral and bacterial infections through modulation of the TLR signaling pathway. Thus, manipulation of 14-3-3 proteins may represent novel therapeutic targets for inflammatory conditions and infections.

SUBMITTER: Butt AQ 

PROVIDER: S-EPMC3493911 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature