Biochemistry & Pharmacology: Open Access
Open Access

Abstract

Statins Downregulate the Constitutive Expression of HLA-DR and Reduce Intracellular CD74 in the Monocyte Cell Line Mono Mac 6

Stefan U Weber, Lutz E Lehmann, Makbule Kobilay, Frank Stüber and Andreas Hoeft

Background: Statins exert immune effects and have been shown to strongly inhibit the interferon-γ induced expression of the human leukocyte antigen (HLA) DR. Monocyte HLA-DR is decreased severe in sepsis and indicates hypo inflammatory and immunosuppressive phases. The aim of the study was to investigate the statin-induced regulation of constitutive HLA-DR expression on monocytes.
Method: Monocytes and the monocyte cell line Mono Mac 6 were incubated with simvastatin, mevastatin, pravastatin and fluvastatin. HMG-Coenzyme A reductase was inhibited by l-mevalonate. Protein expression of HLA-DR, Major histocompatibility complex, invariant CD74 and apoptosis were measured by flow-cytometry. mRNA expression was assessed by PCR.
Results: Simvastatin dose dependently reduced the constitutive HLA-DR expression on monocytes starting from 500 nM. Bypassing statin-induced inhibition of HMG- Coenzyme A reductase reversed this effect. HLA-DR was also decreased in response to mevastatin, pravastatin, lovastatin and fluvastatin after 24 h. Simvastatin induced caspase-3 activation and DNA-fragmentation in a small subpopulation of Mono Mac 6 cells. HLA-DR expression was lower on apoptotic cells, but simvastatin also reduced HLA-DR on non-apoptotic cells. Simvastatin did no repress HLA-DR mRNA. For transferring HLADR to endosomes the chaperon CD74 is required. Intracellular CD74 was decreased by simvastatin and fluvastatin.
Conclusion: Statins decrease the constitutive expression of MHC II on monocytes and Mono Mac 6 independently of apoptosis. Reduced intracellular levels of the chaperon CD74 by statins may potentially impede HLA-DR surface expression.