Elevated glucose levels stimulate transforming growth factor-beta 1 (TGF-beta 1), suppress interleukin IL-2, IL-6 and IL-10 production and DNA synthesis in peripheral blood mononuclear cells.

The molecular mechanisms leading to impaired immune response in less well controlled diabetic patients are unclear. In this study we have analyzed the effects of elevated glucose concentration on both DNA synthesis and the production of transforming growth factor-beta 1 (TGF-beta 1) and the interleukins (IL) IL-2, IL-6 and IL-10 in stimulated peripheral blood mononuclear cells (PBMC) obtained from normal individuals. PBMC were stimulated by pokeweed mitogen or anti-CD3-antibody which binds specifically to the CD3-surface protein of T-lymphocytes. High glucose concentrations significantly inhibited DNA synthesis in PWM- as well as anti-CD3-stimulated PBMC. Exposure to elevated glucose levels caused a significant and dose-dependent increase in the production of latent TGF-beta 1 by (PWM)-stimulated PBMC at 24 and 48 h. Production of the cytokines IL-2, IL-6 and IL-10 was suppressed by elevated glucose concentration dose- and time-dependently. In contrast to the time-dependent decreased effect of glucose-induced TGF-beta 1 production the effects of elevated glucose levels on IL-2, IL-6 and IL-10 production increased with time indicating that TGF-beta 1 production is preceding the reduced IL production. These data demonstrate for the first time that elevated glucose levels significantly alter cytokine production in stimulated peripheral mononuclear cells and concomitantly inhibit cellular proliferation. Our results indicate that high glucose-induced TGF-beta 1 production may suppress immune response by inhibiting the endogenous production of IL-2, IL-6 and IL-10.