Abstract
Inhibitors of the enzymatic activity of alanyl-aminopeptidases severely affect growth and typical functions of human peripheral T cells both in vitro and in vivo. The most prominent changes observed include the activation of cellular signal transduction pathways such as MAP kinases Erk1/2 or the Wnt-pathway, a decrease of production and release of “pro-inflammatory” cytokines (IL-2, IL-12) and, most importantly, an induction of expression and release of the immunosuppressive cytokine, TGF-β1. Similar effects on T cell proliferation and function have been observed in response to inhibition of DPIV, which is strongly suggestive of a functional synergism of APN and DPIV. In support of this hypothesis evidence is provided showing that the simultaneous application of inhibitors of DPIV and APN further enhances the anti-inflammatory and immunosuppressive effects provoked by the inhibition of APN or DPIV alone. Therefore, the simultaneous inhibition of these enzymes represents a promising strategy for the pharmacological therapy of T cell mediated diseases such as autoimmune disease, inflammation, allergy, and allograft rejection.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Boyum, A., 1968, Isolation of mononuclear cells and granulocytes from human blood, Scand. J. Clin. Lab. Invest. (suppl.) 97: 77–89
Furtado, G.C. et al., 2001, Regulatory T cells in spontaneous autoimmune encephalomyelitis, Immunol. Rev. 182: 122–134
Gorelik, L. and Flavell, R.A., 2002, Nature Rev. Immunol. 2: 46–53
Hooper, N.M., 1994, Families of zinc metalloproteases, FEBS Lett. 354: 1–6
Julius, M.H., et al., 1973, A rapid method for the isolation of functional thymus-derived murine lymphocytes, Eur. J. Immunol. 3: 645
Kähne, T., et al., 1999, Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth, Int. J. Mol. Med. 4: 3–15
Lendeckel, U., et al., 1996, Induction of the membrane alanyl aminopeptidase gene and surface expression in human T-cells by mitogenic activation, Biochem. J. 319: 817–823
Lendeckel, U., et al., 1998, Inhibition of alanyl aminopeptidase induces MAP-kinase p42/ERK2 in the human T cell line KARPAS-299, Biochem Biophys Res Commun 252: 5–9
Lendeckel, U., et al., 1999, Role of alanyl aminopeptidase in growth and function of human T cells (review), Int. J. Mol. Med. 4: 17–27
Lendeckel, U., et al., 2000, Inhibition of alanyl-aminopeptidase suppresses the activation-dependent induction of glycogen synthase kinase-3β (GSK-3β) in human T cells, Bioch. Biophys. Res. Commun. 273: 62–65
Lerche, C., et al., 1996, Human aminopeptidase N is encoded by 20 exons, Mammalian Genome 7: 712–713
Look, A.T., et al., 1986, Molecular cloning, expression, chromosomal localization of the gene encoding a human myeloid membrane antigen (gp150), J. Clin. Invest. 78: 914–921
Nakamura, K., et al., 2001, Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta, J. Exp. Med. 194: 629–644
Pontoux, C., et al., 2002, Natural CD4 CD25(+) regulatory T cells control the burst of superantigen-induced cytokine production: the role of IL-10, Int. Immunol. 14: 233–239
Riemann, D., et al., 1995, Stimulation of the expression and the enzyme activity of aminopeptidase N/CD13 and dipeptidylpeptidase IV/CD26 on human renal cell carcinoma cells and renal tubular epithelial cells by T cell-derived cytokines, such as IL-4 and IL-13, Clin. Exp. Immunol. 100: 277–283
Riemann, D., et al., 1993, Demonstration of CDl3/aminopeptidase N on synovial fluid T cells from patients with different forms of joint effusions, Immunobiol. 187: 24–35
Riemann, D., et al., 1994, Immunophenotype of lymphocytes in pericardial fluid from patients with different forms of heart disease, Int. Arch. Allergy Immunol. 104: 48–56
Shapiro, L., 1991, Separate promoters control transcription of the human aminopeptidase N gene in myeoloid and intestinal epithelial cells, J. Biol. Chem. 266: 11999–12007
Singh, B., et al, 2001, Control of intestinal inflammation by regulatory T cells, Immunol. Rev. 182: 190–200
Steinbrecher, A., et al., 2001, Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo, J. Immunol 166: 2041–2048
Tung, K.S., et al., 2001, Regulatory T cell, endogenous antigen and neonatal environment in the prevention and induction of autoimmune disease, Immunol. Rev. 182: 135–148
Watt, V.M., and Willard, H.F., 1990, The human aminopeptidase N gene: isolation, chromosome localization, and DNA polymorphism analysis, Hum. Genet. 85: 651–654
Wex, T., et al., 1997, The activation-dependent induction of APN (CD13) in T cells is controlled at different levels of gene expression, FEBS Lett. 412: 53–56
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Kluwer Academic Publishers
About this chapter
Cite this chapter
Lendeckel, U. et al. (2004). Synergistic Action of DPIV and APN in the Regulation of T Cell Function. In: Back, N., Cohen, I.R., Kritchevsky, D., Lajtha, A., Paoletti, R. (eds) Dipeptidyl Aminopeptidases in Health and Disease. Advances in Experimental Medicine and Biology, vol 524. Springer, Boston, MA. https://doi.org/10.1007/0-306-47920-6_16
Download citation
DOI: https://doi.org/10.1007/0-306-47920-6_16
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-306-47717-1
Online ISBN: 978-0-306-47920-5
eBook Packages: Springer Book Archive