Modulation of neuropeptide Y and norepinephrine on several leucocyte functions in adult, old and very old mice
Introduction
There is a large body of evidence concerning the bidirectional communication between the nervous and the immune system (Besedovsky and Del Rey, 1996, Elenkov et al., 2000). The nervous system regulates the immune system through the innervation of lymphoid organs, in which the neurotransmitters released reach the immune cells. The immune organs show important innervation by sympathetic nerve fibers (Elenkov et al., 2000) and two neurotransmitters released by these fibers, namely norepinephrine (NE) and the neuropeptide Y (NPY), find specific receptors on the immune cells (De la Fuente, 1999, Elenkov et al., 2000, Kohm and Sanders, 2001, Sanders and Straub, 2002).
With ageing, there is a progressive disruption of the neuroimmune communication which has been associated with functional alterations observed in the elderly (Fabris, 1991, Straub et al., 2001). Furthermore, age-related changes observed in leucocyte subsets from peripheral blood have been related to morbidity and mortality in the aged (Wikby et al., 1998, Huppert et al., 2003), and it is accepted that an age-related impairment in lymphocyte functions, especially in T-cell activities, occurs. In old age, a decrease in lymphoproliferative capacity as well as in the production of IL-2 (Medina et al., 2000, Lord et al., 2001, Straub et al., 2001, De la Fuente, 2002, Douziech et al., 2002) and natural killer (NK) activity (Ferrández et al., 1999, De la Fuente et al., 2001b, Straub et al., 2001, De la Fuente, 2002) has been found. Regarding TNF-α, an increase in the release of this pro-inflammatory cytokine with age has been observed (De la Fuente et al., 2001a, Lord et al., 2001, Straub et al., 2001). All these changes are less evident in those individuals who are 100 years of age or older (Aspinall, 2000). For instance, it appears that T cells from centenarians are fully capable of proliferating like those of younger individuals, showing only a short delay in reaching peak responsiveness (Franceschi et al., 1995, Sansoni et al., 1997).
Several functions of the cellular immune system have been shown to be regulated by NPY (De la Fuente et al., 1993, De la Fuente et al., 2001a, De la Fuente et al., 2001b, De la Fuente, 1999, Medina et al., 1998, Medina et al., 1999, Medina et al., 2000, Bedoui et al., 2003) and NE (Ortega et al., 2000a, Ortega et al., 2000b, Kohm and Sanders, 2001, Sanders and Straub, 2002) and the effects of these neurotransmitters on leucocyte functions depend on the subject age (De la Fuente et al., 2000, De la Fuente et al., 2001a, De la Fuente et al., 2001b, Medina et al., 2000, Ortega et al., 2000a, Ortega et al., 2000b).
Since both neurotransmitters are co-released in vivo by the same sympathetic nerve endings, the aim of the present study was to investigate the age-related changes in the in vitro effects of both NPY and NE, jointly, on several peritoneal leucocyte functions such as lymphoproliferation in response to mitogen, natural killer activity and IL-2 and TNF-α release from adult (24 ± 2 weeks), old (72 ± 2 weeks) and very old (28 ± 2 weeks) mice. In addition this work was aimed to investigate if, as it has been shown in human centenarians, the above immune functions are better preserved in the very old mice than in old animals, as well as if the effects of NPY and NE are different in cells from old and very old mice.
Section snippets
Animals and experimental conditions
Female BALB/c (Harlam Interfauna Ibérica, Barcelona, Spain) mice (Mus musculus) were bred until the ages of 24 ± 2 (adult), 72 ± 2 (old) and 128 ± 2 (very old) weeks. The animals were housed in groups of 7–9 individuals per cage and maintained at a constant temperature of 21 ± 1 °C and reverse 12:12-h dark–light cycle (lights on at 20:00 h), with free access to food (A04 diet from Panlab, Barcelona, Spain) and water. The mice were checked periodically to verify their pathogen-free condition and the
Results
Fig. 1 shows changes with ageing in several leucocyte functions. There was a decrease in proliferative capacity in response to mitogens Con A and LPS in old and very old mice, the last animals showing a proliferative response higher than the old mice (Fig. 1A). IL-2 release and NK activity (Fig. 1B and C) and TNF-α release (Fig. 1D) decreased and increased, respectively, in old mice but not in very old animals, which showed similar levels of these functions to those observed in adult mice.
Discussion
It is commonly accepted that lymphocytes are the immune cells most affected by ageing. In the present work, we have observed an impairment of the lymphoproliferative response to mitogens (Concanavalin A and LPS) in old mice, in agreement with other authors (Pawelec et al., 2002, Douziech et al., 2002, Frasca et al., 2003) and with previous work from our group (De la Fuente et al., 2000, Guayerbas et al., 2002). The very old mice showed a higher lymphoproliferative capacity in response to
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