Serum amyloid A induces interleukin-6 in dermal fibroblasts via Toll-like receptor 2, interleukin-1 receptor-associated kinase 4 and nuclear factor-κB.
Systemic sclerosis is an autoimmune idiopathic connective tissue disease, characterized by vasculopathy, inflammation and fibrosis. There appears to be a link between inflammation and fibrosis, although the exact nature of the relationship is unknown. Serum amyloid A (SAA) is an acute-phase protein that is elevated up to 1000-fold in times of infection or inflammation. This acute-phase reactant, as well as being a marker of inflammation, may initiate signals in a cytokine-like manner, possibly through toll-like receptors (TLRs) promoting inflammation. This study addressed the role of SAA in initiating interleukin-6 (IL-6) production in dermal fibroblasts and the role of TLR2 in this system. We show that SAA induces IL-6 secretion in healthy dermal fibroblasts and that blockade of TLR2 with a neutralizing antibody to TLR2 or specific small interfering RNA attenuated the SAA-induced IL-6 secretion and that this was also mediated through the TLR adaptor protein IL-1 receptor-associated kinase 4. The effect is nuclear factor-κB-mediated because blockade of nuclear factor-κB reduced the induction. We also demonstrate that dermal fibroblasts express TLR2; this is functional and over-expressed in the fibroblasts of patients with systemic sclerosis. Taken together these data suggest that SAA is a danger signal that initiates IL-6 signalling in systemic sclerosis via enhanced TLR2 signalling.
Musculoskeletal Research Group, Institute of Cellular Medicine, Middlesbrough, UK.
Steven
S
O'Reilly
Rachel
R
Cant
Marzena
M
Ciechomska
James
J
Finnigan
Fiona
F
Oakley
Sophie
S
Hambleton
Jacob M
JM
van Laar
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism* / Q000494:pharmacology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D016328:NF-kappa B; D000685:Serum Amyloid A Protein; D051195:Toll-Like Receptor 2; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
Toll-like receptor 2; danger signal; interleukin-6; serum amyloid A