In vivo suppression of NK cell cytotoxicity by stress and surgery: Glucocorticoids have a minor role compared to catecholamines and prostaglandins

Abstract

Most in vitro and ex-vivo studies indicate a profound suppression of NK cell cytotoxicity (NKCC) by glucocorticoids; while catecholamines and prostaglandins were reported both to suppress and to enhance NKCC. However, methodological considerations hinder our ability to deduce from these findings to the impact of endogenous release of these factors on in vivo levels of NKCC and their implications to NK-dependent resistance to pathologies in living humans or animals. Here we used an in vivo approach that sensitively and specifically reflects NKCC in living F344 rats, based on lung clearance of NK-sensitive tumor cells (MADB106), and based on comparing effects between NK-intact and NK-depleted rats. To study the role of corticosterone, epinephrine, and prostaglandins, we administered these factors to rats, or antagonized their endogenous release following different stress paradigms or surgery. The results indicated that endogenous or exogenous elevated corticosterone levels can suppress in vivo NKCC levels, but only under some conditions, and mostly secondarily to the NK-suppressing impact of epinephrine. Specifically, corticosterone-induced NKCC suppression occurred (i) only under prolonged, but not short exposure to stress, and mainly in males; (ii) was smaller than the prominent impact of epinephrine; (iii) was mostly ascribed to corticosterone-induced potentiation of the effects of epinephrine or/and prostaglandins; and (iv) was completely abolished through antagonizing epinephrine or/and prostaglandins. Overall, these findings markedly limit the significance of stress/surgery-induced corticosterone release in the in vivo suppression of NKCC, and highlight the blockade of epinephrine or/and prostaglandins as effective and clinically feasible approaches to overcome such immuno-suppressive effects.

Innate immune function after breast, lung, and colorectal cancer surgery

“…In 2 of the 3 groups of patients in our study, we observed an increase in the postoperative plasma concentrations, and those undergoing chronic BB therapy experienced a smaller postoperative decrease in the NK cell function. Similar results have been demonstrated in experimental studies, but the actual relevance of our findings may be illustrated by the results in a recent publication by Rosenne et al, who demonstrated that catecholamines are significant contributors to low NKCC after laparotomy in animals, although this phenomenon only partially explains the protumoral effects of surgery [10,12,22,23].…”

The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity

“…Specifically, this may occur through a more prolonged exposure, which was evident herein to exert a direct in vitro NK suppressive effects in the presence of plasma, and was reported by in vivo studies [16]. Additionally, suppression of NKCC may occur through (i) indirect effects of stress hormones on NKCC, such as through reduction in Th1 cytokine levels [43], (ii) through direct suppression of NKCC by catecholamines and PGs when locally released at supra-systemic levels [26, 32–34], and/or (iii) through suppression of non-circulating unique NK cell subpopulations [44–46] of different susceptibility to stress hormones.…”

“…However, several ex-vivo studies in humans and animals have suggested that no such suppression occurs in vivo [21, 22], and a recent in vivo animal study has supported this suggestion, indicating specific conditions under which corticosterone may exerts some effects [16]. …”

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

“…Activation of the sympathetic nervous system leads to release of stress hormones such as epinephrine and norepinephrine (NE), which signal via adrenergic receptors on tumor cells, resulting in diminished efficacy of conventional chemotherapy and promotion of tumor metastasis, inflammation, and other prosurvival pathways (6)(7)(8)(9)(10)(11)(12). Although molecular events that have direct effects on tumor cells have been well documented, the effects of adrenergic signaling on the tumor stroma are not well understood.…”