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Interfering with Proximal TLR4 to NF-kappaB Signal Transduction in Human Monocytes

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-1beta, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kappaB binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkappaBalpha in human monocytes, thereby inhibiting NF-kappaB signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-kappaB activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE16193 | GEO | 2010/05/21

SECONDARY ACCESSION(S): PRJNA117203

REPOSITORIES: GEO

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Project description:Inflammation is a hallmark of multiple disease processes, including inflammatory bowel disease (IBD). The transcription factor NF-kappaB plays a critical role in this response through its effects on pro-inflammatory gene expression. Consequently, homeostatic mechanisms that control NF-kappaB activity have been found to play important roles in controlling inflammatory responses in physiologic and pathologic states. Copper Metabolism Murr1 Domain containing 1 (COMMD1), a regulator of copper excretion and other transport pathways, has been shown to play a role in limiting NF-kappaB activation. However, it remains unclear if this factor plays a necessary role in the control of inflammation or in the pathogenesis of inflammatory disorders in vivo. Using a myeloid-cell specific model of Commd1 deficiency in mice we evaluated the contribution of this factor to inflammatory responses. We found that this gene plays an important role as a negative regulator of the LPS transcriptional response, and deficiency in this factor led to sensitization to in vivo models of sepsis. In addition, we identified single nucleotide variants located near COMMD1 that are associated with decreased expression of this gene in humans. Interestingly, these polymorphisms also show a suggestive association signal with ulcerative colitis risk. Consistent with the possibility that genetic variation in COMMD1 expression may predispose to colitis, we find that myeloid deletion of Commd1 leads to more severe colonic inflammation and cancer progression in experimental colitis models. Altogether, the data support the notion that COMMD1 expression in myeloid cells plays an important anti-inflammatory role in physiologic states and human disease. Bone marrow derived macrophages (BMDM) were isolated from two individual wildtype - and two Commd1 knockout mice. Cells from individual mice were splitted and were treated with LPS for 3h, 24h, or, were left untreated. The corresponding 12 cell samples were subjected to total RNA preparation and subsequently used for Single-Color-based Microarray Analysis (Agilent Technologies).

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Interfering with Proximal TLR4 to NF-kappaB Signal Transduction in Human Monocytes

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