Polymorphisms in IL-2, IL-6, IL-10, and IFN-gamma genes are associated with their protein production after anti-CD3/CD28 stimulation. The profound effect of the IL-2 gene polymorphism in homozygous individuals may serve as a marker for those that could mount the most vigorous allo- or autoimmune responses, or perhaps become tolerant more easily.

Polymorphisms in the regulatory regions of cytokine genes are associated with high and low cytokine production and may modulate the magnitude of alloimmune responses following transplantation. Ethnicity influences allograft half-life and the incidence of acute and chronic rejection. We have questioned whether ethnic-based differences in renal allograft survival could be due in part to inheritance of cytokine polymorphisms. To address that question, we studied the inheritance patterns for polymorphisms in several cytokine genes (IL-2, IL-6, IL-10, TNF-a, TGF-b, and IFNg) within an ethnically diverse study population comprised of 216 Whites, 58 Blacks, 25 Hispanics, and 31 Asians. Polymorphisms were determined by allele-specific polymerase chain reaction and restriction fragment length analysis. We found striking differences in the distribution of cytokine polymorphisms among ethnic populations. Specifically, significant differences existed between Blacks and both Whites and Asians in the distribution of the polymorphic alleles for IL-2. Blacks, Hispanics and Asians demonstrated marked differences in the inheritance of IL-6 alleles and IL-10 genotypes that result in high expression when compared with Whites. Those of Asian descent exhibited an increase in IFN-g genotypes that result in low expression as compared to Whites. In contrast, we did not find significant ethnic-based differences in the inheritance of polymorphic alleles for TNF-a. Our results show that the inheritance of certain cytokine gene polymorphisms is strongly associated with ethnicity. These differences may contribute to the apparent influence of ethnicity on allograft outcome.

ObjectiveC-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.MethodsThe time course of IL-6 and MCP-1 production was determined in whole blood incubated with saline, 1 µg/mL lipopolysaccaride (LPS), 50 and 100 µM/L DL-homocysteine, and 5 µg/mL human recombinant CRP for 24 hours at 37°C under 5% CO2 atmosphere. Cytokine responses were determined in blood drawn from 15 healthy volunteers before and after administration of pravastatin 40 mg daily for 2 days.ResultsBoth 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.ConclusionsCRP 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.