title: The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis.
abstract: The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA.
authors.affiliation: Kennedy Institute of Rheumatology, Imperial College London, and the Department of Orthopedics, Royal United Hospital, Bath, UK.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sacre
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
authors.forename: Serafim
authors.initials: S
authors.lastname: Kiriakidis
authors.forename: Parisa
authors.initials: P
authors.lastname: Amjadi
authors.forename: Anna
authors.initials: A
authors.lastname: Lundberg
authors.forename: Grey
authors.initials: G
authors.lastname: Giddins
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Fionula
authors.initials: F
authors.lastname: Brennan
authors.forename: Brian M
authors.initials: BM
authors.lastname: Foxwell
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020782:Matrix Metalloproteinases