Peer-Reviewed Journal Details
Mandatory Fields
Ahmed, S;Maratha, A;Butt, AQ;Shevlin, E;Miggin, SM
2013
March
Journal of Immunology
TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15
Published
26 ()
Optional Fields
MYELOID DENDRITIC CELLS ADAPTER PROTEIN TRIF TOLL-LIKE RECEPTOR-3 NF-KAPPA-B MATRIX METALLOPROTEINASES CYTOPLASMIC DOMAIN GENE INDUCTION PATHWAY ACTIVATION EXPRESSION
190
2217
2228
TLRs are a group of pattern-recognition receptors that play a crucial role in danger recognition and induction of the innate immune response against bacterial and viral infections. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-kappa B and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling. To this end, TRIF-interacting partners were identified by immunoprecipitation of the TRIF signaling complex, followed by protein identification using liquid chromatography mass spectrometry. Following stimulation of cells with a TLR3 or TLR4 ligand, we identified a disintegrin and metalloprotease (ADAM) 15 as a novel TRIF-interacting partner. Toward the functional characterization of the TRIF: ADAM15 interaction, we show that ADAM15 acts as a negative regulator of TRIF-mediated NF-kB and IFN-beta reporter gene activity. Also, suppression of ADAM15 expression enhanced polyriboinosinic polyribocytidylic acid and LPS-mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced rhinovirus 16 and vesicular stomatitis virus-mediated proinflammatory cytokine production. Interestingly, ADAM15 mediated the proteolytic cleavage of TRIF. Thus, ADAM15 serves to curtail TRIF-dependent TLR3 and TLR4 signaling and, in doing so, protects the host from excessive production of proinflammatory cytokines and matrix metalloproteinases. In conclusion, to our knowledge, our study clearly shows for the first time that ADAM15 plays an unexpected role in TLR signaling, acting as an anti-inflammatory molecule through impairment of TRIF-mediated TLR signaling. The Journal of Immunology, 2013, 190: 2217-2228.
BETHESDA
0022-1767
10.4049/jimmunol.1201630
Grant Details