Modulation of neuropeptide Y and norepinephrine on several leucocyte functions in adult, old and very old mice

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Abstract

The age-related changes in the communication between the nervous and the immune system have been scarcely investigated, especially in very aged subjects. The present work deals with the in vitro effects of norepinephrine and neuropeptide Y, separately and jointly, on functions such as lymphoproliferation, NK activity, and IL-2 and TNF-α release of peritoneal leucocytes from adult (24 ± 2 weeks), old (72 ± 2 weeks) and very old (128 ± 2 weeks) mice. The old mice showed a decrease in proliferation, NK activity and IL-2 release, and an increase in TNF-α, whereas in the very old mice these functions were more similar to those of the adults. The effects of neurotransmitters on these functions were different depending on the age of the animals.

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

References (48)

  • G. Di Lorenzo et al.

    Granulocyte and natural killer activity in the elderly

    Mech. Ageing Dev.

    (1999)
  • N. Douziech et al.

    Modulation of human lymphocyte proliferative response with aging

    Exp. Gerontol.

    (2002)
  • M.D. Ferrández et al.

    Effects in vitro of several antioxidants on natural killer function on aging mice

    Exp. Gerontol.

    (1999)
  • A. Fiserová et al.

    Effects of D2-dopamine and α-adrenoceptor antagonists in stress induced changes on immune responsiveness of mice

    J. Neuroimmunol.

    (2002)
  • C. Franceschi et al.

    The immunology of exceptional individuals: the lesson of centenarians

    Immunol. Today

    (1995)
  • C. Franceschi et al.

    The network and the remodeling theories of aging: historical background and new perspectives

    Exp. Gerontol.

    (2000)
  • D. Frasca et al.

    Effects of aging on proliferation and E47 transcription factor activity induced by different stimuli in murine splenic B cells

    Mech. Ageing Dev.

    (2003)
  • T. Fülop et al.

    Cyclodextrin modulation of T lymphocyte signal transduction with aging

    Mech. Ageing Dev.

    (2001)
  • A. Globerson et al.

    Ageing of lymphocytes and lymphocytes in the aged

    Immunol. Today

    (2000)
  • N. Guayerbas et al.

    Leukocyte function and life span in a murine model of premature immunosenescence

    Exp. Gerontol.

    (2002)
  • K. Hirokawa

    Age-related changes of signal transduction in T cells

    Exp. Gerontol.

    (1999)
  • F.A. Huppert et al.

    Survival in a population sample is predicted by proportions of lymphocyte subsets

    Mech. Ageing Dev.

    (2003)
  • J.M. Lord et al.

    Neutrophil ageing and immunesenescence

    Mech. Ageing Dev.

    (2001)
  • S. Medina et al.

    Changes with ageing in the modulation of murine lymphocyte chemotaxis by CCK-8s, GRP and NPY

    Mech. Ageing Dev.

    (1998)
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