The Study Of The Mechanism Of IL-18 Upregulates The CSF-1 Gene Transcription

IL-18 is a member of the IL-1 cytokine family serving as a potent and indispensable inflammatory factor. IL-18 promotes the innate immunity as well as the adaptive immunity mediated by Th1 and Th2 cells. IL-18 stimulates the cytokine production of the immune cells, antagonizing infection of bacteria and fungi as well as suppressing the tumor growth. IL-18 is also involved in many chronic inflammation and auto-immune diseases such as: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes and atherosclerosis, promoting inflammation and impairing health. The multi-biological functions of IL-18 are mediated by the interaction between IL-18 and its receptor IL-18R, which belongs to the IL-1 receptor/Toll like receptor (TLR) superfamily. To initiate the signal transduction, IL-18R forms the heterodimer with right conformation, interactes with the TIR domain of the MyD88 homodimer which is an adaptor protein, then recruits the downstream signal molecules and finally activates NF-КB and MAPK, promoting the expression of other inflammatory factors.The inflammatory immune cells secrete colony-stimulating factor-1 (CSF-1), accelerating the activation and proliferation of mono-nuclear macrophage, promoting the adhesion of leukocyte to the vessel epithelia and stimulating production of some cytokines and growth factors to regulate the inflammation. Playing an important role in atherosclerosis and many other immune diseases, CSF-1 can be identified as a potential marker for inflammation and disease. Analysis of the CSF-1 promoter sequence reveals that NF-КB, AP-1 and Sp-1 may be involved in the regulation of CSF-1 via the potential cis-elements.In our previous studies, we reported that the activative leukocytes secrete the inflammatory factor CSF-1 in the earlier period of inflammation. So,we investigated whether IL-18 promoted inflammation via regulation of CSF-1 expression and by what mechanism CSF-1 was regulated by IL-18. Our results showed that IL-18 up-regulated the expression of CSF-1 by the activation of NF-КB via the MyD88 dependent signaling pathway. We hypothesized the binding of NF-КB to the promoter of CSF-1 to up-regulate the expression of CSF-1. Our work provided an insight into the signal transduction mechanism of IL-18R,as well as the biological significance of IL-18, helping people find the key point of the signal pathway to provide new effective therapeutic targets.