Effect of neuropeptide Y on inflammatory paw edema in the rat: involvement of peripheral NPY Y1 and Y5 receptors and interaction with dipeptidyl-peptidase IV (CD26) Mirjana Dimitrijevic ´ a, * , Stanislava Stanojevic ´ a , Vesna Vujic ´ b , Vesna Kovac ˇevic ´-Jovanovic ´ a , Annette Beck-Sickinger c , Hans-Ulrich Demuth d , Stephan von Ho ¨rsten e a Immunology Research Center ‘‘Branislav Jankovic ´’’, Institute of Immunology and Virology ‘‘Torlak’’, Vojvode Stepe 458, 11152 Belgrade, Yugoslavia b Institute of Chemistry, School of Medicine, Belgrade, Yugoslavia c Department of Biochemistry, University of Leipzig, 04103 Leipzig, Germany d Probiodrug Research, Biocenter, Weinbergweg 22, 06120 Halle an der Saale, Germany e Department of Functional and Applied Anatomy, OE 4120, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany Received 3 January 2002; received in revised form 17 May 2002; accepted 22 May 2002 Abstract Several lines of evidence suggest that neuropeptide Y (NPY) may exert regulatory effects in local inflammatory responses. Here, we show that intraplantarly (i.pl.) applied NPY, peptide YY (PYY), and an NPY Y5 receptor-selective agonist dose-dependently potentiate concanavalin A (Con A)-induced paw edema in the rat. The NPY Y1 receptor antagonist BIBO 3304 abolishes the pro-inflammatory action of both NPY and PYY while the dipeptidyl-peptidase IV (CD26) inhibitor Ile-thiazolidide exerted synergistic and potentiating effects in vivo. Taken together, the present data reveal an NPY Y1/Y5 receptor interplay and an involvement of CD26 in the NPY-induced potentiation of paw edema in the rat. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Neuropeptide Y (NPY); NPY receptors; Dipeptidyl-peptidase IV (DPIV, CD26); Paw edema; Inflammation; Rats 1. Introduction Neuropeptide Y (NPY) is widely distributed throughout central and peripheral nervous systems and exhibits a variety of biological functions including regulation of food intake, memory retention, blood pressure, cardiac contrac- tility, and anxiety (Wettstein et al., 1995; Kalra et al., 1999; Renshaw and Hinson, 2001). Recent advances in the molec- ular biology of the receptors for NPY have resulted in the identification of at least five receptor subtypes (Y1, Y2, Y4, Y5, and Y6) with varying peptide pharmacology (Michel et al., 1998; Gehlert, 1998). Brain NPY has been related to the regulation of the inflammatory response in the periphery, since dose-depend- ent and receptor-specific effects on granulocyte and NK cell function have been demonstrated (Ho ¨rsten et al., 1998a,b) that partly mimic the known immunomodulatory effects of centrally applied met-enkephalin (Ho ¨rsten et al., 1998c). Recently, several reports described the antinociceptive activ- ity of centrally applied NPY in carrageenan-induced paw inflammation that was mediated through Y1 receptor (Wang et al., 2001; Naveilhan et al., 2001). Analgesic properties of NPY are explained by the inhibition of substance P release from the sensory neurons (Walker et al., 1988). In the periphery, NPY is found in the sympathetic nervous system, co-stored, and co-released with norepi- nephrine (Ekblad et al., 1984; Zukowska-Grojec, 1998). NPY causes vasoconstriction by direct effects on Y1 recep- tors expressed on vascular smooth muscles and potentiates norepinephrine-evoked vasoconstriction postjunctionally. Initial studies dealing with NPY and immunity revealed inhibitory action of NPY on antibody production in the rat. (Friedman et al., 1995) and negative correlation between circulating levels of NPY and NK cell activity in humans (Irwin et al., 1991). Intravenous application of NPY exerts dose- and leukocyte subset-specific effects on blood leuko- 0165-5728/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S0165-5728(02)00173-X * Corresponding author. Tel.: +381-11-467-465; fax: +381-11-471-838. E-mail address: ilijadim@EUnet.YU (M. Dimitrijevic ´). www.elsevier.com/locate/jneuroim Journal of Neuroimmunology 129 (2002) 35 – 42