Reduction in toll-like receptor-4 (tlr-4) on blood mononuclear cells after 3 weeks of rosuvastatin treatment in healthy male subjects

Purpose: Rosuvastatin is a statin drug with major benefits in dyslipidemia. It may share many of the pleiotropic effects of this drug class one of which is a potential anti-inflammatory effect. One of the proposed anti-inflammatory mechanisms of statins is to modulate tlr-4 (LPS receptor) expression and a resulting reduction in the production of TNF-alpha and other anti-inflammatory cytokines.

Methods: This study evaluated tlr-4 expression on blood mononuclear cells and plasma inflammatory cytokine concentrations before and after 3 weeks of rosuvastatin in 20 healthy male subjects. Plasma cytokine concentrations were analyzed before and after incubating blood samples with LPS. IL-8, sCD14, IL-6, IGF-1, and TNF-alpha were measured by sandwich-type ELISA (R&D Systems). The density of tlr-4 was measured using single color flow cytometry gating on mononuclear cell fraction with appropriate isotype controls.

Results: Sixteen of twenty consented male patients between the ages of 22 to 38 years (avg. 27 years) were evaluable. Four subjects did not meet stringent inclusion criteria having minor elevations in bilirubin. The expression of tlr-4 on blood mononuclear cells was significantly lower after 3 weeks of rosuvastatin (p = 0.046). TNF-alpha release associated with ex-vivo treatment of blood with LPS trended lower after 3 weeks of rosuvastatin treatment (p = 0.08). None of the other inflammatory markers (CRP, IL-8, sCD14, IL-6, and IGF-1) were modified with rosuvastatin treatment. There was a significant decline in cholesterol (p<0.0001), LDL (p<0.0001), and cholesterol/HDL ratio (p<0.0001). However, there was no significant effect on triglycerides, VLDL, or HDL.

Conclusion: The decline in the percentage of blood mononuclear cells expressing tlr-4 and the near significant decline in plasma TNF levels after 3 weeks of rosuvastatin suggest a potential anti-inflammatory activity. The anti-inflammatory effect occurs on a similar timeline as its cholesterol lowering effects.