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Regulatory Effects of 1,25-Dihydroxyvitamin D₃ on the Cytokine Production of Human Peripheral Blood Lymphocytes¹

Institute of General and Experimental Pathology (M.W., R.T., K.S., E.B., M.H., R.G., K.B., P.P., O.S., M.P.) and the Department of Gastroenterology and Hepatology (W.R.), Clinic of Internal Medicine IV, University of Vienna, Vienna, Austria

Address all correspondence and requests for reprints to: Martin Willheim, M.D., Institute of General and Experimental Pathology, AKH Wien, Waehringer Guertel 18–20, A-1090 Vienna, Austria. E-mail: martin.willheim{at}akh-wien.ac.at

We studied the possible regulatory effects of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] on cytokine production and differentiation of subsets of CD4⁺ [T helper 1 (Th1) and Th2] and CD8⁺ [T cytotoxic 1 (Tc1) and Tc2] lymphocytes at the single cell level. PBMC from healthy donors were cultured with or without 1,25-(OH)₂D₃ for up to 21 days. On days 0, 7, 14, and 21, the percentage of cytokine-producing T lymphocytes was analyzed by intracellular cytokine detection with mAb and flow cytometry. Simultaneous staining for cell surface markers allowed discrimination of CD4⁺ and CD8⁺ T cell subsets. After culture with 1,25-(OH)₂D₃ (10^-8 mol/L), no significant effects on the proportion of interferon- (IFN)- or interleukin-4 (IL-4)-producing cells were detected, whereas reduced frequencies of IL-2-producing cells in the CD4⁺ as well as in the CD8⁺ population were found. An increase in the low percentage of CD4⁺ and CD8⁺ T cells producing the Th2 cytokine IL-13 was noticed. Most interestingly, IL-6-producing CD4⁺ and CD8⁺ T cells could only be detected in cultures with 1,25-(OH)₂D₃, reaching a plateau after 14 days. The percentage of IL-6-producing T cells induced by 1,25-(OH)₂D₃ after a given time period remained stable for at least 7 weeks. Studies of cytokine coexpression revealed that about 70% of IL-6-producing CD4⁺ and CD8⁺ cells were also positive for IL-2, but more than 90% were negative for IFN, IL-4, or IL-13, respectively. This suggests that the IL-6-producing population does not match the Th1/Tc1-like (IFN⁺) or Th2/Tc2-like (IL-4⁺ or IL-13⁺) subset. The influence of 1,25-(OH)₂D₃ on cytokine production by lymphocytes is probably an important point of intersection between the endocrine and the immune system.

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