Nitric Oxide Modulates MCP-1 Expression in Endothelial Cells: Implications for the Pathogenesis of Pulmonary Granulomatous Vasculitis

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Inflammation (Impact Factor: 2.21). 09/2003; 27(4):213-23. DOI: 10.1023/A:1025036530605
Source: PubMed


Monocyte chemoattractant protein-1 (MCP-1) is a pivotal mediator of angiocentric granuloma formation in glucan-induced pulmonary granulomatous vasculitis. Based on the rationale that mononuclear phagocytes retrieved from granulomas are rich sources of nitric oxide (NO) and that the recruitment of mononuclear phagocytes into lesions abates as granuloma formation slows, we tested the hypothesis that MCP-1 gene expression is regulated by a NO-sensitive mechanism. Preexposure of endothelial cell (EC) monolayers to NO donor compounds markedly reduced cytokine-induced MCP-1 expression and cytosolic-to-nuclear translocation of nuclear factor-kappa B (NF-kappaB), reversed fluctuations in endothelial reduced glutathione (GSH) pools but did not affect cGMP concentrations. The lungs of mice bearing targeted disruptions of the inducible nitric oxide synthase (iNOS) gene exhibited significantly higher concentrations of MCP-1 following glucan infusion than did those of wild-type mice. Cumulatively, these data suggest that NO suppresses MCP-1 expression by blunting the redox changes associated with cytokine-induced EC activation.

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    • "Monocytes and, to a lesser extent, granulocytes secrete MCP-1 in response to cytokines, viruses, bacterial endotoxins, and mitogens [55]. In vitro studies have shown that NO donors (NONOate compounds) inhibit the expression and production of MCP-1 in cytokine-activated human endothelial cells [56]. In addition, inhibition of endogenous NO synthesis by L-NNA increased endothelial MCP-1 mRNA expression and resulted in a marked increase in monocyte chemotactic activity [57], suggesting that NO modulates MCP-1 expression and activity in vitro. "
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    ABSTRACT: Some evidence indicates that nitric oxide (NO) contributes to inflammation, while other evidence supports the opposite conclusion. To clarify the role of NO in inflammation, we studied carrageenin-induced pleurisy in rats treated with an NO donor (NOC-18), a substrate for NO formation (L-arginine), and/or an NO synthase inhibitor (S-(2-aminoethyl) isothiourea or N(G)-nitro-L-arginine). We assessed inflammatory cell migration, nitrite/nitrate values, lipid peroxidation and pro-inflammatory mediators. NOC-18 and L-arginine reduced the migration of inflammatory cells and edema, lowered oxidative stress, and normalized antioxidant enzyme activities. NO synthase inhibitors increased the exudate formation and inflammatory cell number, contributed to oxidative stress, induced an oxidant/antioxidant imbalance by maintaining high O(2) (-), and enhanced the production of pro-inflammatory mediators. L-arginine and NOC-18 reversed the proinflammatory effects of NO synthase inhibitors, perhaps by reducing the expression of adhesion molecules on endothelial cells. Thus, our results indicate that NO is involved in blunting-not enhancing-the inflammatory response.
    Mediators of Inflammation 06/2010; 2010(4):682879. DOI:10.1155/2010/682879 · 3.24 Impact Factor
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    • "A possible feedback loop for Th2 activation would be the production of IL-4 and IL-13 by Th2, which stimulates MCP-1 production and leads to further recruitment of Th2 cells [37]. NO increases the ability of monocytes to respond to chemotactic agents more eVectively , and it is considered to be one of the principal eVector molecules involved in macrophage-mediated cytotoxicity [38]. Previous studies suggest that magnetic Welds are involved in the alteration of NO production, probably related to a constitutive form of NOS rather than to an inducible form [39] [40]. "
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    ABSTRACT: The purpose of this study was to investigate whether overnight exposure to 1 mT-50 Hz extremely low-frequency sinusoidal electromagnetic field (EMF) affects the expression and production of inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1) in human monocytes. RT-PCR and Western blot analysis demonstrate that EMF exposure affects the expression of iNOS and MCP-1 in cultured human mononuclear cells at the mRNA level and protein synthesis. Interestingly, the effects of EMF exposure clearly differed with respect to the potentiation and inhibition of iNOS and MCP-1 expression. Whereas iNOS was down-regulated both at the mRNA level and at the protein level, MCP-1 was up-regulated. These results provide helpful information regarding the EMF-mediated modulation of the inflammatory response in vivo. However, additional studies are necessary to demonstrate that EMF acts as a nonpharmacological inhibitor of NO and inducer of MCP-1 in some diseases where the balance of MCP-1 and NO may be important.
    Nitric Oxide 09/2006; 15(1):50-7. DOI:10.1016/j.niox.2005.11.010 · 3.52 Impact Factor
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    ABSTRACT: Vasculitis refers to a number of distinct disease entities characterized by cellular inflammation within and adjacent to the blood vessel wall.1 Typically, there is destruction of the vessel but leukocytoclastic vasculitis exhibits only leukocytic infiltrates within the vessel wall. Multiple classification schemes have been proposed to categorize this group of diseases (Table 59.1). Lung involvement is most common in primary idiopathic, small vessel, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides of Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.2 However, medium vessel vasculitis of classic polyarteritis nodosa, large and medium vessel vasculitis of Takayasu’s arteritis (causing associated pulmonary hypertension), primary immune complex-mediated vasculitis of Goodpasture’s syndrome, and lupus erythematosus can all affect the lungs. The pulmonary circulation is characterized by low perfusion pressure, and large- and medium-sized pulmonary arteries are shorter in length and contain less elastin than in the systemic circulation; these factors apparently limit involvement of the larger pulmonary vessels by vasculitis. Table 59.1. Classification of pulmonary vasculitides based on size of the vessel involved.
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