engleski

Regulation of dipeptyl peptidase IV (DPPIV/CD26) on human dermal fibroblasts by endomorphin-2

DPPIV is a broadly distributed membrane non-classical serine protease that cleaves dipeptides from N-terminal of the polypeptides if proline (or alanine) is at the penultimate position. It is a multifunctional molecule. In addition to the enzyme activity, DPPIV can act as an adhesive molecule and as a costimulatory molecule transducing the growth-promoting signal. Its expression is regulated by cytokines (IL-1-alpha, IL-12, TNF-alpha) and glucocortiocoids. Neuropeptides can also regulate the expression of membrane enzymes that in turn cleave the neuropeptides (Bae SJ et al., Int Arch Allergy Immunol 127:316, 2002). We examined whether opioid peptide endomorphin-2 (Tyr-Pro-Phe-Phe-NH2 ; E-2) (highly selective for mu opioid receptors), which is a physiological DPPIV substrate, could affect the expression of DPPIV on human dermal fibroblasts. The role of the cleavage site in the interaction was examined by using a synthetic tetrapeptideTyr-D-Pro-Phe-Phe-NH2 (DE-2), which is resistant to cleavage by DPPIV. The role of mu-opioid receptors was examined by using an opioid receptor antagonist, naloxone. DPPIV enzyme activity was measured by means of hydrolysis of fluorochrome-labeled substrate and by immunohistochemical staining with anti-CD26 antibodies. The data have shown time- and concentration-dependent up-regulation of DPPIV with both endogenous E-2 (DPPIV sensitive) and synthetic DE-2 (DPPIV resistant). However, naloxone abrogated or diminished only the effects of DPPIV-resistant DE-2, suggesting that E-2 and DE-2 may use different mechanisms in regulating DPPIV. The mechanisms could be, respectively, an interaction with the enzyme cleavage site or binding to the opioid receptor. Collectively, the data show that endomorphin-2 can up-regulate DPPIV expression on dermal fibroblasts either via an interaction with the enzyme itself or via the opioid receptor. Increased DPPIV expression on fibroblasts may affect their functional activity and growth.

dipeptidyl peptidase IV; CD26; endomorphin-2; fibroblasts

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