David I. Beller

Immunosuppression in mice induced by cold water stress.

A number of studies indicate that stress can result in suppression of the immune system in animals and man. Most of the studies have focused on alterations of lymphocyte function while only a few have investigated alterations of macrophage function or macrophage cytokine production. Macrophages play an essential role in homeostasis of the immune response. Indeed, the earliest events of the immune response occur in cells of the monocytic lineage, and their secretion of various cytokines may have both immunological and nonimmunological effects. The present studies were undertaken to determine whether alterations in macrophage physiology occur in mice subjected to a stress stimulus. Our studies in mice exposed to cold water stress for 4 days indicated reduced numbers of thymocytes and splenocytes, decreased T-cell blastogenesis, and reduced NK activity. Examination of elicited peritoneal macrophages from stressed mice revealed increased prostaglandin E2 (PGE2) secretion and decreased immune region associated antigen (Ia) expression in response to interferon-gamma. Despite elevated PGE2 levels, indomethacin was generally unable to restore depressed immune function. Of special interest was the finding that cell-associated and secreted interleukin 1 were significantly higher from unstimulated elicited macrophages from stressed mice. These results suggest that early in the response to stress, functions of a variety of cells within the immune system, especially macrophages, are altered and that dysregulated macrophage function may well contribute to the generalized suppression of the immune response in cold water stressed mice.

Substance P and Stress‐Induced Changes in Macrophagesa

The present paper further links nervous-endocrine-immune systems by describing influences of SP on the immune system, and more specifically, on macrophage function. We have discussed how macrophages are important to immune responses in that much of cellular and humoral responses depend on macrophage function. Macrophages are sensitive to stress in that cold-water stress causes increased cytokine production, either spontaneously (IL-1), or after induction with LPS (IL-6, TNF alpha). Increased cytokine levels (IL-1, IL-6) may induce acute phase reactants in the liver, which is presumably the mechanism operative in the studies indicating increases in acute phase reactants after certain stressors in animals. SP is a likely candidate to affect immune function. Previous data show that macrophages from various species have receptors for and respond to SP in vitro. SP stimulates phagocytic and chemotactic capacity, as well as increased cytokine, PGE2, and thromboxane B2 production. SP is also involved in neurogenic inflammation and is likely to be involved in the pathogenesis of several inflammatory diseases. Present data indicate SPs involvement in macrophage responses to stress. We have shown that stress induced differential SP receptor binding to peritoneal macrophages, although the precise nature of binding differences has not yet been clearly elucidated. Stress also induces more immunoreactive SP in the peritoneal fluid that bathes the peritoneal macrophages. We hypothesize that the two events, altered SP binding and concomitant increased ligand, are causally related. In addition to other correlational data showing concomitant increased SP binding plus ligand concentrations, there is more direct evidence that SP ligand may induce SP receptor expression since the SP antagonist, CP-96,345, prevents the induction of SP receptor mRNA in the staphylococcal toxin A-induced gastroenteritis (C. Pothoulakis and S. E. Leeman, personal communication). Further supporting our notion for a causal relationship we have found the elimination of SP in vivo (via capsaicin pretreatment) reduced SP binding, as has been previously reported. We have also examined the role of SP on stress-induced altered macrophage function in vitro. SP greatly enhanced the LPS-induced macrophage TNF alpha production from stressed animals; in contrast, it produced relatively little effect on macrophages from control animals. Capsaicin pretreatment diminished the enhanced cytokine production in response to stress, such that levels of TNF alpha and IL-6 approximated those of control mice. Taken together, past and present data suggest that (1) stress may initiate, or at least contribute to, an inflammatory response, and that (2) SP is involved in the macrophage stress response. SP has long been known to be involved in inflammatory processes; our data further suggest its role in mediating stress-induced cytokine alterations.