PMID- 17575266 OWN - NLM STAT- MEDLINE DCOM- 20071025 LR - 20171116 IS - 0741-5400 (Print) IS - 0741-5400 (Linking) VI - 82 IP - 3 DP - 2007 Sep TI - The extra domain A of fibronectin stimulates murine mast cells via toll-like receptor 4. PG - 657-65 AB - The activation of mast cells by extra domain A of fibronectin (FN-EDA), an endogenous ligand of TLR4, and its contribution to the pathogenesis of rheumatoid arthritis (RA) in vivo were examined. FN-EDA, but no other domain of the fibronectin fragment, III(11) (FN-III(11)) and III(12) (FN-III(12)), stimulated bone marrow-derived murine mast cells (BMMCs) dose-dependently to secret cytokines (TNF-alpha, IL-6, and IL-1beta), similar to the pattern produced by LPS. FN-EDA-induced cytokine production was mediated by TLR4, as cytokine production by FN-EDA was absent in TLR4-deficient (TLR4-/-) BMMCs. We examined the roles of TLR4-mediated mast cell activation by this form of fibronectin fragment in the pathogenesis of RA in vivo. The injection of FN-EDA, but not FN-III(11)and FN-III(12), to joints resulted in joint swelling of mice in vivo. Genetically mast cell-deficient WBB6F(1)-W/W(v) mice exhibited significantly less swelling and cytokine production compared with mast cell-sufficient +/+ mice, suggesting that swelling and inflammatory cytokine production were partially dependent on tissue mast cells. Reduced swelling and cytokine production were recovered by the reconstitution of tissue mast cells by the injection of BMMCs from wild-type mice but not from TLR4-/- mice. Altogether, these results suggest that the TLR4-mediated activation of mast cells by endogenous ligand FN-EDA might contribute to the pathogenesis of RA through proinflammatory cytokine production. FAU - Gondokaryono, Srie Prihianti AU - Gondokaryono SP AD - Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. FAU - Ushio, Hiroko AU - Ushio H FAU - Niyonsaba, Francois AU - Niyonsaba F FAU - Hara, Mutsuko AU - Hara M FAU - Takenaka, Hiroshi AU - Takenaka H FAU - Jayawardana, Sumanasiri T M AU - Jayawardana ST FAU - Ikeda, Shigaku AU - Ikeda S FAU - Okumura, Ko AU - Okumura K FAU - Ogawa, Hideoki AU - Ogawa H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070615 PL - England TA - J Leukoc Biol JT - Journal of leukocyte biology JID - 8405628 RN - 0 (Fibronectins) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Recombinant Proteins) RN - 0 (Tlr2 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 2) RN - 0 (Toll-Like Receptor 4) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.2.1.52 (beta-N-Acetylhexosaminidases) SB - IM MH - Animals MH - Arthritis, Rheumatoid/etiology/metabolism/pathology MH - Blotting, Western MH - Bone Marrow/metabolism/pathology MH - Fibronectins/genetics/*pharmacology MH - Inflammation/etiology/pathology MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - Joints/metabolism/pathology MH - Lipopolysaccharide Receptors/metabolism MH - Lipopolysaccharides/pharmacology MH - Mast Cells/*drug effects/metabolism MH - Mice MH - Mice, Knockout MH - NF-kappa B/metabolism MH - Protein Structure, Tertiary MH - Recombinant Proteins/metabolism MH - Toll-Like Receptor 2/metabolism MH - Toll-Like Receptor 4/*metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - beta-N-Acetylhexosaminidases/metabolism EDAT- 2007/06/19 09:00 MHDA- 2007/10/27 09:00 CRDT- 2007/06/19 09:00 PHST- 2007/06/19 09:00 [pubmed] PHST- 2007/10/27 09:00 [medline] PHST- 2007/06/19 09:00 [entrez] AID - jlb.1206730 [pii] AID - 10.1189/jlb.1206730 [doi] PST - ppublish SO - J Leukoc Biol. 2007 Sep;82(3):657-65. doi: 10.1189/jlb.1206730. Epub 2007 Jun 15.