The effect of homocysteine on the production of inflammatory cytokines

Abstract

Elevated C-reactive protein (CRP), homocysteine and inflammatory cytokines such as interleukin-6 (IL-6) are associated with increased cardiovascular risk. CRP has direct inflammatory actions stimulating the production of IL-6 and monocyte chemoattactant protein-1, (MCP-1) in whole blood. Homocysteine increases the production of MCP-1 and IL-8 in endothelial cellsin vitro, but whether it has direct inflammatory actions in an environment more representative of in vivo biology, is not known. Thus, we examined the hypothesis that homocysteine would stimulate the production of IL-6 and MCP-1 in whole blood. Blood was drawn from 15 healthy subjects and incubated with saline, 1μg/ml lipopolysaccaride (LPS), 50 (n=8) and 100 μM/L (n=6) DL-homocysteine or 5 μg/ml human recombinant CRP for 24 hours. Both CRP and LPS significantly increased the production of IL-6 and MCP-1 more than 4-fold (P<0.001) but homocysteine did not. Homocysteine had little effect on IL-6 (fold change at 24 hours 1.4±0.4 (SEM) vs. baseline, P=0.14) or MCP-1 (0.9±4.5, P=0.08) production. Thus, concentrations of homocysteine that had inflammatory effects in vitro, and are in the range that occur in patients with hyperhomocystinemia had no effect on IL-6 or MCP-1 production in whole blood. A possible explanation is that the whole blood environment provides antioxidant defenses not present in cell culture and may thus attenuate the inflammatory effects of homocysteine, thought to be mediated by free radicals. Clinical Pharmacology & Therapeutics (2004) 75, P49–P49; doi: 10.1016/j.clpt.2003.11.184