Joint disease caused by defective gp130-mediated STAT signaling
AUTOR(ES)
Naka, Tetsuji
FONTE
BioMed Central
RESUMO
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 (gp130ΔSTAT/ΔSTAT), 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 gp130ΔSTAT/ΔSTAT mouse. These findings may be beneficial in the elucidation of the cause and the treatment of rheumatoid arthritis in humans.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=128925Documentos Relacionados
- STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line.
- Suppressor of cytokine signaling-3 is a biomechanical stress–inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways
- STAT protein complexes activated by interferon-gamma and gp130 signaling molecules differ in their sequence preferences and transcriptional induction properties.
- Defective STAT signaling by the leptin receptor in diabetic mice.
- Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.