Der Einfluss von Vitamin D auf das angeborene Immunsystem

The innate immune system plays a crucial role in defending the organism from invading pathogens in a non-specific manner. The well-orchestrated regulation of its function is vital for the integrity of the organism. Different endogenous factors (e.g. hormones or cytokines) as well as exogenous factors (e.g. cigarette smoke or environmental toxins) can influence this complex equilibrium. The regulation of calcium and phosphate metabolism has been considered as one of the classical functions of vitamin D. It is only in recent years that its meaning for the physiology of the innate and adaptive immune system was recognized. The exact molecular mechanisms, how vitamin D exerts its effect as an immune modulator, are only partly understood. The aim of this work was to characterize the influence of vitamin D on human macrophages and neutrophil granulocytes after contact with bacterial pathogens. Possible interactions between the observed vitamin-D-effect and cigarette smoke were analyzed. Human macrophages and neutrophil granulocytes were incubated with different concentrations vitamin D and TLR ligands. The bacterial elimination rate, the production of the only known human antimicrobial peptide hCAP-18/LL-37 (LL-37) and the changes in cytokine response were examined using a bacterial killing assay, ELISA qRT-PCR and western blot. The cell lines U937 as well as MonoMac6 and murine peritoneal macrophages were stimulated under the same conditions used for primary human cells and the obtained results were compared. In order to examine the interaction between cigarette smoke and vitamin D, primary human macrophages were incubated with both substances and the effects on the synthesis of LL-37 as well as the expression of proinflammatory cytokines were determined. It could be shown that vitamin D has an antimicrobial and antiinflammatory impact on the innate immune functions. In macrophages and neutrophil granulocytes the induction of LL-37 is increased while the release of proinflammatory cytokines is decreased. This is accompanied with an enhancement of the bacterial elimination rate. Significant effects are detected for concentrations above the current recommendations for sufficient vitamin-D-levels from the Institutes of Medicine. Summary IV The comparison between different model systems showed that vitamin D does not increase the synthesis of the murine LL-37-homolog mCRAMP. In human cell lines the expression of LL-37 is increased but there is no influence on the cytokine response. Cigarette smoke interferes with the efficacy of vitamin D as an immune modulator. It inhibits the vitamin-D-mediated antimicrobial effect without any influence on the antiinflammatory cytokine depression. The results of this work underline the importance of vitamin D for the physiology of the immune system. Its impact on the synthesis of endogenous antibiotics and the inflammation reaction offers an interesting starting point for the development of new therapy strategies. The analysis of dose-effect relationship in synopsis with current epidemiological data as well as the shown interaction between cigarette smoke and vitamin D could play a crucial role for primary preventive health care.