carbon monoxide blocks lipopolysaccharide-induced gene expression by interfering with proximal tlr4 to nf-κb signal transduction in human monocytes一氧化碳块lipopolysaccharide-induced基因表达通过干扰近端在人类单核细胞tlr4 nf-κb信号转导.pdfVIP

Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-kB Signal Transduction in Human Monocytes 1 1 1 1 2 Maneesha Chhikara , Shuibang Wang , Steven J. Kern , Gabriela A. Ferreyra , Jennifer J. Barb , Peter J. 2 1 Munson , Robert L. Danner * 1 Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America Abstract Carbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1b, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kB binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkBa in human monocytes, thereby inhibiting NF-kB signal transduction. CO broadly suppresses the initial inflammatory response of human monocy