Frob se et al. reported that SOCS 3 inhibited the IL 1B induced activity of TAK 1 in INS 1 cells, a rat pancreatic B cell line. Furthermore, SOCS1 was able to inhibit both MAPK and NF ��B signaling pathways in our models. Thus, we e amined the effects of SOCS1 on TAK1 activ ity. Stable SOCS1 overe pression did not alter TAK1 phosphorylation levels selleck chemicals after IL 1B treatment. Une pectedly, however, the levels of total TAK1 de creased in the SOCS1 overe pressing cells in a gene dose dependent manner. Because SOCS1 degrades intracellular proteins via ubiquitination, the ubiquitination level of TAK1 was investigated. Lysates of the SOCS1 overe pressing cells were immunoprecipitated by using anti TAK1 antibodies.
The SOCS1 overe pression led to a higher level of TAK1 ubiquitination after IL 1B stimulation, suggesting TAK1 ubiquitination as a mechanism by which SOCS1 decreases the TAK1 levels. Additionally, when the SOCS1 overe pressing SW1353 cells were e posed to MG132, a proteasome inhibitor, TAK1 levels were increased in a time and concentration dependent manner. Discussion Cartilage damage in OA has been considered a result of an imbalance between catabolic and anabolic processes. A large body of the evidence reveals that proinflammatory cytokines are present in the synovial membrane and cartil age, even in the early stage of OA, and they function as major mediators of cartilage destruction. IL 1B is be lieved to play a vital role as a major catabolic factor in OA cartilage. However, anti IL 1B therapy, such as anakinra, did not provide any significant clinical benefit in OA patients.
Furthermore, parado ically, the IL 1B deficient mice accelerated a posttraumatic or spontaneous OA, and the IL 6 deficient male mice developed spontan eous knee OA. These findings suggest that IL 1B and IL 6 parado ically have a joint protective role by a secondary regulatory system that counteracts the catabolic effects of inflammation. One such candidate is SOCS, which inhibits cellular inflammatory response as a cytokine inducible negative regulator of cytokine signal ing. Interestingly, concerning the gender effect in IL 6 deficient mice, it was reported that estrogen or pro gesterone could increase the e pression levels of SOCS1. Indeed, e pression of SOCS1 was increased in OA cartilage in parallel to damage severity, and SOCS1 e pression was directly induced by IL 1B in human articular chondrocytes in our study.
Our e periments clearly showed suppressive effects of SOCS1 on IL 1B induced MMPs and ADAMTS 4 production in human chondro cytes in both SOCS1 overe pression and knockdown sys tems. These findings suggest that IL 1B inducible SOCS1 acts Entinostat as a negative regulator of IL 1B in human chondro cytes in OA pathogenesis, and the absent efficacy of anti IL 1B treatment could, in part, result from the loss of this chondroprotective role of SOCS1. In addition, Fan et al.