Alanyl-Aminopeptidases in Human T Cells

Abstract

Inhibition of the enzymatic activity of alanyl-aminopeptidase leads to strong immunosuppression both in vitro and in vivo. Mechanisms involved include growth arrest, induction of immunosuppressive cytokines (TGF-13I), reduced expression of inflammatory or T cell stimulating cytokines (IL-2, IL-12) , and modulation of T cell signalling pathways. Thus, T cells appear to represent a major cellular target for the pharmacological treatment of T cell mediated diseases by virtue of aminopeptidase inhibitor administration. Membrane (APN) and cytosol alanyl-aminopeptidase (ApPS), both implicated in a variety of cellular functions, show similar substrate specifity and inhibitor sensitivity. Furthermore, both enzymes are expressed in practically all T cell subsets, including the population of natural regulatory T cells that was shown recently to control the immunological tolerance to self-antigens. While the involvement of APN and ApPS in the pathological immune response is evident, the precise molecular mechanisms remain to be identified. The development of inhibitors specific for APN and ApPS is an attractive field of study and would allow determination of the individual contribution of either enzyme in the immune response.

Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/ CD13) — A novel approach for the treatment of inflammatory bowel disease

“…Most interestingly, both, the inhibition of DPIV or APN, leads to an increasing transcription, synthesis and secretion of the most potent immunosuppressive cytokine TGFβ1, suggesting that both enzymes plays a key role in limiting and terminating immune activation [11][12][13][14]. Moreover, APN inhibitors were recently found to be capable of preserving and promoting the suppressive activity of CD4+CD25 bright T regulatory cells [15].…”

Dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) as regulators of T cell function and targets of immunotherapy in CNS inflammation

“…The specific APN inhibitors actinonin and probestin caused a dose-dependent suppression of DNA synthesis of stimulated human T cells and PBMC [9,18,19]. Moreover, these inhibitors were shown to suppress the IL-1β and IL-2 production of stimulated human PBMC and T cells [9,18,19]. In parallel to DP IV inhibitors, both actinonin and probestin were shown to be capable of inducing TGF-β1 expression in human PBMC and T cells [9,18,19].…”

“…Moreover, these inhibitors were shown to suppress the IL-1β and IL-2 production of stimulated human PBMC and T cells [9,18,19]. In parallel to DP IV inhibitors, both actinonin and probestin were shown to be capable of inducing TGF-β1 expression in human PBMC and T cells [9,18,19].…”

“…The specific APN inhibitors actinonin and probestin caused a dose-dependent suppression of DNA synthesis of stimulated human T cells and PBMC [9,18,19]. Moreover, these inhibitors were shown to suppress the IL-1β and IL-2 production of stimulated human PBMC and T cells [9,18,19].…”

Dual Inhibition of Dipeptidyl Peptidase IV and Aminopeptidase N Suppresses Inflammatory Immune Responses

“…APN/CD13 inhibitors have been also developed and tested for their immunomodulatory activity on leukocyte functions. The specific APN inhibitors actinonin and probestin caused a dose‐dependent suppression of DNA synthesis of mitogen‐stimulated human T cells and PBMCs 9,18,19 . Moreover, these inhibitors were shown to suppress the IL–1β and IL‐2 production of stimulated human PBMCs and T cells 9,18,19 .…”