Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor‐β₁ in PWM‐stimulated PBMC and T cells

Abstract

Various studies have shown that the membrane ectoenzyme dipeptidyl peptidase IV (DPIV; CD26), expressed on T, natural killer (NK) and B cells in the immune system, is involved in the regulation of DNA synthesis and cytokine production. We show that the specific DP IV inhibitors Lys[ Z(NO2)]‐thiazolidide, Lys[Z(NO2)]‐piperidide, and Lys[Z(NO2)]‐pyrrolidide inhibit DNA synthesis as well as production of interleukin‐2 (IL‐2), IL‐10, IL‐12, and interferon‐γ (IFN‐γ) of pokeweed mitogen (PWM)‐stimulated purified T cells. Most importantly, these inhibitors induce a three‐ to fourfold increased secretion of latent transforming growth factor‐β1 (TGF‐β1) by PWM‐stimulated peripheral blood mononuclear cells (PBMC) and T cells, as measured with a specific TGF‐β1 enzyme‐linked immunosorbent assay and in the Mv1Lu bioassay. As we could demonstrate previously, TGF‐β1 exhibits the same 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‐β1 antibody was capable of abolishing the DP IV inhibitor‐induced suppression of DNA synthesis of PWM‐stimulated PBMC and T cells. These data suggest that TGF‐β1 might have key functions in the molecular action of DP IV/CD26 in regulation of DNA synthesis and cytokine production.

Targeting Dipeptidyl Peptidase IV (CD26) Suppresses Autoimmune Encephalomyelitis and Up-Regulates TGF-β1 Secretion In Vivo

“…Recently, it has been demonstrated in vitro that DP IV inhibition induces a severalfold increase in TGF-␤1 mRNA and protein in polyclonally stimulated T cells (33,35). Anti-TGF-␤1 neutralized the effect of DP IV inhibition on the proliferation of PWM-stimulated human T cells (35). We extend these findings, demonstrating for the first time that anti-TGF-␤1 can also block the effect of DP IV inhibition on Ag-specific T cell proliferation.…”

“…We demonstrate furthermore that I40 increases the secretion of latent TGF-␤1 by Ag-stimulated LNC populations. Recently, it has been demonstrated in vitro that DP IV inhibition induces a severalfold increase in TGF-␤1 mRNA and protein in polyclonally stimulated T cells (33,35). Anti-TGF-␤1 neutralized the effect of DP IV inhibition on the proliferation of PWM-stimulated human T cells (35).…”

“…These data confirm and extend earlier reports showing that DNA synthesis and the secretion of IL-2, IL-6, and IL-10 from mouse spleen cells and thymocytes (33) are suppressed by DP IV inhibitors. Likewise, in human T cells proliferation and the secretion of various cytokines including TNF-␣ and IFN-␥ were suppressed (34,35). It is widely accepted that EAE can be mediated by Th1 CD4 ϩ T cells typically secreting IFN-␥, TNF-␣, and lymphotoxin.…”

“…They specifically and dose-dependently suppress proliferation and secretion of various cytokines by human and murine T cells (32)(33)(34). Interestingly, it is well documented that these inhibitors also induce a 3-to 4-fold increase in the secretion of latent TGF-␤1 by mitogen-stimulated murine and human T cells (33,35).…”

CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

“…Furthermore, we have previously shown that DPPIV enzyme activity is partially involved in the costimulatory activity of CD26 through studies using wild-type CD26 (DPPIV + ) or mutant CD26 (DPPIV 2 )-transfected Jurkat T cell lines (55). Other groups reported that the synthetic competitive DPPIV inhibitor Lys[Z(NO 2 )] significantly suppressed the proliferation and production of IL-2, IL-10, and IFN-g in PWM-stimulated human T cells (56). They showed that these DPPIV inhibitors markedly increased the secretion of latent TGF-b1 by PWM-stimulated T cells, resulting in suppression of T cell activation.…”