INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV INDUCE SECRETION OF TRANSFORMING GROWTH FACTOR-BETA(1) IN PWM-STIMULATED PBMC AND T-CELLS

Various studies have shown that the membrane ectoenzyme dipeptidyl pep tidase IV (DP IV; CD26), expressed on T, natural killer (NK) and B cel ls in the immune system, is involved in the regulation of DNA synthesi s and cytokine production. We show that the specific DP IV inhibitors Lys[Z(NO2)]-thiazolidide, Lys[Z(NO2)]-piperidide, and Lys [Z(NO2)]-pyr rolidide inhibit DNA synthesis as well as production of interleukin-2 (IL-2), IL-10, IL-12, and interferon-gamma (IFN-gamma) of pokeweed mit ogen (PWM)-stimulated purified T cells. Most importantly, these inhibi tors induce a three- to fourfold increased secretion of latent transfo rming growth factor-beta(1) (TGF-beta(1)) by PWM-stimulated peripheral blood mononuclear cells (PBMC) and T cells, as measured with a specif ic TGF-beta(1) enzyme-linked immunosorbent assay and in the Mv1Lu bioa ssay. As we could demonstrate previously, TGF-beta(1) exhibits the sam e inhibitory effects as DP IV inhibitors on DNA synthesis and cytokine production (Cytokine 1994, 6, 382-8; J Interferon Cytokine Res 1995, 15, 685-90). A neutralizing chicken anti-TGF-beta(1) antibody was capa ble of abolishing the DP IV inhibitor-induced suppression of DNA synth esis of PWM-stimulated PBMC and T cells. These data suggest that TGF-b eta(1) might have key functions in the molecular action of DP IV/CD26 in regulation of DNA synthesis and cytokine production.