Effects of C-reactive Protein and Homocysteine on Cytokine Production: Modulation by Pravastatin

Abstract

OBJECTIVE: C-reactive protein (CRP) and homocysteine are markers of cardiovascular risk that may have inflammatory effects. HMG coenzyme A reductase inhibitors (statins) have anti-inflammatory effects in vitro, but it is not clear if such responses in vivo are secondary to lipid lowering. We examined the hypothesis that CRP and homocysteine would stimulate cytokine release in human whole blood and that short-term treatment with a statin would inhibit it. METHODS: The time course of IL-6 and MCP-1 production was determined in whole blood incubated with saline, 1 microg/mL lipopolysaccaride (LPS), 50 and 100 microM/L DL-homocysteine, and 5 microg/mL human recombinant CRP for 24 hours at 37 degrees C under 5% CO(2) atmosphere. Cytokine responses were determined in blood drawn from 15 healthy volunteers before and after administration of pravastatin 40 mg daily for 2 days. RESULTS: Both human recombinant CRP and LPS significantly increased the production of IL-6 and MCP-1 in whole blood samples more than 4-fold (P < 0.001) but homocysteine did not. Oral administration of pravastatin, 40mg daily for 2 days, decreased CRP-stimulated IL-6 production by approximately 20% (P = 0.02) 6 hours after incubation, but did not affect MCP-1 production (P = 0.69). Pravastatin treatment did not affect LPS-stimulated MCP-1 but increased IL-6 modestly. CONCLUSIONS: CRP stimulated the production of the proatherogenic mediators MCP-1 and IL-6 in human whole blood, but homocysteine did not. CRP-stimulated production of IL-6, but not MCP-1, was modestly attenuated by short-term treatment with pravastatin.

Figure 2

Effect of pravastatin on IL-6 production in whole blood during stimulation with 5 g/mL recombinant CRP for 6 hours (n = 15). Administration of pravastatin reduced CRP-stimulated IL-6 production by an average of –20% (P= 0.02).

Figure 1

(a) Time course of IL-6 production in whole blood. (b) Time course of MCP-1 production in whole blood. LPS and recombinant CRP induced IL-6 and MCP-1 release in whole blood culture. Data are expressed as mean ± SEM. *P < 0.001 compared with control (IL-6 and MCP-1 production in unstimulated whole blood).