Commentary on Exercise and Neuroendocrine Regulation of Immune Responses

The papers by Fleshner [2], Jonsdottir [5] and Woods [14] provide timely reviews of neuroendocrine regulation of specific immune responses with acute exercise and training. As pointed out in these reviews, the evidence for neuroendocrine modulation comes from studies of identification of opioid and ß₂- adrenergic receptors on lymphocytes and NK cells, studies showing adrenergic and peptidergic innervation of lymphoid tissues, and by blockade studies using in vitro antagonists and inhibitors. While these classical neuroendocrine pathways are fundamental to understanding exercise as a stress modality, other regulatory components inform the immune response to exercise.

These other components include paracrine regulation and juxtacrine regulation. Paracrine regulation of immune cell functions with exercise was first described by Blank and colleagues [1] using NK cell cytolytic activity in treadmill-trained mice. Although Blank suggested that such regulation lies in the interaction between macrophages and NK cells, paracrine regulation could include any extra-neuroendocrine tissue, with local secretion of hormones and neuropeptides such as ß-endorphin, growth hormone and prolactin. Exercise elevates the concentrations of ß-endorphin, growth hormone and prolactin in plasma. While there is limited work in the area of paracrine regulation of NK cells by opioid hormones, stimulation of thymocytes and peripheral T lymphocytes by mitogens (and presumably antigens) results in the expression of prolactin isoforms [13] and the appearance of immunoreactive prolactin detected by Western blotting [7]. Moreover, since some of these hormones appear to work with cytokines (e.g., prolactin and IL-2 synergize to induce proliferation and activation of lymphokine-activated killer cells), it is important to determine the functional interaction and the signal transduction cascades linking hormone-receptor interaction to target cytokine gene activation following exercise.

A second consideration in the neuroendocrine regulation of immune responses with exercise is that of juxtacrine regulation. Juxtacrine regulation refers to cell-to-cell interactions in which one cell signals a target cell, with the signaling molecule remaining fixed to the plasma membrane of the signaling cell rather than being released into the fluid phase [15]. This type of strict spatial regulation of immune cell function has been called 'tethering and signaling' [12] and is an important mechanism for differential adhesion and activation of leukocytes to a variety of stimuli. The juxtacrine regulation may provide a mediating bridge for neuroendocrine effects on NK cell cytolytic activity. Several groups (e.g., [3] [4]) have demonstrated changes in the expression of cell adhesion molecules with exercise, especially the CD11a/CD18 component of LFA-1 on NK cells and the CD11b/CD18 component of LFA-1 on macrophages. For example, we demonstrated a greater resistance to blockade of CD11a in splenocytes of acute exercised mice; this finding may have been due to a conformational change in CD11a leading to a reduction in antibody binding or to a shedding of the CD11a receptor with a concomitment reduction in receptor-antibody interaction. Further, it is well known that the expression of intercellular adhesion molecules (ICAM-1) can be up-regulated by proinflammatory cytokines (e.g., see reference [11]) and there is evidence that some hormones and neuroendocrine peptides (for example, alpha-MSH) influence the expression of ICAM-1 both directly and indirectly through actions on cytokine stimulation [10]. Interaction between NK cell and macrophage-derived cytokines, adhesion molecules, and autocrine/paracrine hormone costimulatory signals are areas which need to be considered in neuroendocrine regulation.

In commenting on neuroendocrine regulation, an important distinction appears to be that of exercise as a dis-stress and exercise as a eustress. Most exercise immunology research has focused on transient, acute suppression of immune reactions to the dis-stress of exercise; repeated exposure to exercise may be a buffer (a eustress) against heterotypic and novel distress events (e.g., [2] [6]). The neuroendocrine mechanisms here are less well described. Borrowing from the developmental stress psychology literature, the issue of developmental determinants may be instructive to understand how repeated exposure to exercise acts to buffer the immune reaction to stress. Meaney and colleagues [8] demonstrated well over a decade ago that repeated handling (and/or transient, repeated hypothermia) of newborn rats results in less or slower reactivity to later stress and novelty in adult animals. The key mechanistic aspect was later shown to be an enhancement of type II glucocorticoid receptors in the hippocampus with a more efficient termination of the stress response (for example, reference [9]). Whether a similar mechanism operates with repeated early exposure to exercise is an area of future investigation.

In summary, neuroendocrine factors have been demonstrated to be involved in immunoregulation of immune cell cytolytic activity through the classical hypothalamic-pituitary-adrenal axis acting on lymphocyte hormone receptors; there is also evidence of direct sympathetic and parasympathetic innervation of organs of the immune system. Less well studied are the areas of autocrine/paracrine and juxtacrine regulation of cytolytic activity of natural killer and other immune cells. Neuroimmunomodulation with exercise stress could occur through juxtacrine interactions by modulating cytokine effects or directly by influencing intercellular adhesion molecules and immune cell ligand expression. Further, evidence of mRNA for some 'classical' neuropeptide hormones, such as prolactin, has been demonstrated in some T lymphocytes providing a suggestion of potential autocrine and paracrine control of immune functions. Finally, the impact of repeated early exposure to exercise and the buffering response may reflect changes in hippocampal hormonal receptors and slower stress arousal.

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