Joint disease caused by defective gp130-mediated STAT signaling.
IL-6 is a multifunctional cytokine produced by lymphoid and nonlymphoid cells; it regulates immune responses, acute-phase reactions, and inflammation. IL-6 signaling is mediated exclusively by the common signal-transducing component gp130, which is also essential for signal transduction of other cytokines of the leukemia inhibitory factor (LIF)/IL-6 family. M Ernst and colleagues generated and studied knock-in mice (gp130DeltaSTAT/DeltaSTAT), in which all STAT-binding sites (sites binding signal transducers and activators of transcription) were deleted from their gene encoding gp130 but binding sites for both Janus kinases (JAKs) and for the protein tyrosine phosphatase-2 (SHP-2) were preserved. They found that this mutant mouse displayed a blastocyst implantation defect, gastrointestinal ulceration, and, interestingly, severe joint disease with representative features of rheumatoid arthritis. Synovial cells from this mouse exhibited mitogenic hyper-responsiveness to cytokines of the LIF/IL-6 family, a phenomenon that was caused by sustained gp130-mediated SHP-2/Ras/Erk activation due to a defect in the induction of SOCS-1 (suppressor of cytokine signaling-1; also known as SSI or JAB). This suppressor, induced by STAT signaling, regulates cytokine signaling. It is, therefore, conceivable that the disturbance of the balanced activation between the STAT and SHP-2/Ras/Erk signal pathways causes the joint disease in the gp130DeltaSTAT/DeltaSTAT mouse. These findings may be beneficial in the elucidation of the cause and the treatment of rheumatoid arthritis in humans.
Naka
Tetsuji
T
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Japan. naka@imed3.med.osaka-u.ac.jp
Kishimoto
Tadamitsu
T
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D050822:Cytokine Receptor gp130; D004195:Disease Models, Animal; D015536:Down-Regulation; D015850:Interleukin-6 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D012097:Repressor Proteins; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
D015703:Antigens, CD; D002352:Carrier Proteins; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130