Age-related changes in the neuropeptide Y effects on murine lymphoproliferation and interleukin-2 production S. Medina a , M. Del Rı ´o a , A. Hernanz b , M. De la Fuente a, * a Departamento de Biologı ´a Animal II (Fisiologı ´a Animal), Facultad de Ciencias Biolo ´gicas, Universidad Complutense, Madrid, Spain b Servicio de Bioquı ´mica, Hospital La Paz del Insalud, Madrid, Spain Received 17 February 2000; accepted 18 May 2000 Abstract Neuropeptide Y (NPY) modulates several aspects of the immune response but it is not known whether NPY responsiveness is altered with aging. In this work, the in vitro effect of NPY at concentrations ranging from 10 -14 M to 10 -7 M on lymphoproliferation has been studied in spleen, axillary node and thymus leukocytes from young, adult, mature and old BALB/c mice. The spontaneous proliferation of spleen lymphocytes from young mice was significantly stimulated by NPY. In response to the mitogen Con A, lymphoproliferation and IL-2 release by lymphocytes were inhibited significantly by NPY, these effects disappearing with aging. The results show that NPY is a modulator of lymphoproliferation and that this effect disappears progressively with age. Moreover, this regulatory role of NPY may be carried out through a decrease in IL-2 production. © 2000 Published by Elsevier Science Inc. Keywords: Aging; Neuropeptide Y; Lymphoproliferation; IL-2; Mice 1. Introduction Age-related changes in the immune system can result in an inappropriate response to antigens [24,33,37] leading to a greater susceptibility to diseases and death. The involution of the thymus gland is the most obvious age-related change in the immune system [32]. Accordingly, one of the most marker age-related alterations in the immune cells has been reported in the T lymphocytes, concretely in the lympho- proliferative response to mitogens, which is decreased in old subjects and animals [16,37]. Moreover, the low prolifera- tive response of T cells is related to decreased interleukin 2 (IL-2) production, which is involved in the lymphoprolif- erative response to mitogens [16]. The immune system is in close intercommunication with the nervous system, and changes in the relationship between both systems have been regarded as responsible for sys- temic aging [11]. There are studies revealing the presence of sympathetic fibers in both primary and secondary lymphoid organs [40], and changes with aging in this noradrenergic innervation of lymphoid tissues. Moreover, anatomic and biochemical data show sympathetic denervation in the splenic tissue during senescence [1]. Neuropeptide Y (NPY), a peptide from the pancreatic polypeptide (PP) family with an important role as neuro- transmitter and neuromodulator in the nervous system, is released by noradrenergic neurons in addition to norepi- nephrine [15]. NPY is secreted from nerve endings in the peripheral and central nervous system as well as in all the lymphoid organs where T cells reside [40]. Immunochemi- cal studies have revealed the presence of NPY in sympathetic neurons from lymphoid tissue with particularly high concen- trations in spleen [34]. Recent data implicate NPY in the modulation of immune responses in vivo and in vitro. Thus, this neuropeptide decreases or increases immune functions such as antibody responses in rats [14], phagocytic process [7], cytotoxic activity [25], adhesion and migration [22,26], prolif- eration [2,19,27,36] and cytokine secretion [2,21]. The present study examines the changes occurring with age in both types of proliferation, i.e.; spontaneous and in response to the mitogen Con A, of lymphocytes from spleen, axillary nodes and thymus of young, adult, mature and old mice, and the possible immunomodulatory role of NPY on this lymphocyte function. Since IL-2 is an essential cytokine for the control of proliferation and differentiation of immune system cells, and specifically for the lympho- * Corresponding author. Tel.: +34-91-3944989; fax: +34-91-394- 4935. E-mail address: mondelaf@eucmax.sim.ucm.es (M. De la Fuente). Peptides 21 (2000) 1403–1409 0196-9781/00/$ – see front matter © 2000 Published by Elsevier Science Inc. PII: S0196-9781(00)00284-9