Metastatic-promoting effects of LPS: Sexual dimorphism and mediation by catecholamines and prostaglandins

Abstract

Inflammation is implicated in several medical conditions that are sexually dimorphic, including depression, cardiovascular diseases, autoimmunity, and presumably cancer progression. Here we studied the effects of the pro-inflammatory agent, LPS, on MADB106 lung tumor retention (LTR), and sought to elucidate underlying mechanisms and sexual dimorphism. F344 male and female rats were administered with LPS (0.001-1 mg/kg i.v.) simultaneously with tumor cell inoculation, and treated with a β-blocker (nadolol, 0.2-0.3 mg/kg s.c.), a COX-inhibitor (indomethacin, 4 mg/kg s.c.) or both drugs. To study the role of NK cells, numbers and cytotoxicity of marginating-pulmonary NK cells were studied, and selective in vivo NK-depletion was employed. Serum levels of corticosterone, IL-6, and TNF-α were also assessed. The findings indicated that LPS increased LTR in both sexes, but 10-fold higher doses were needed in females to reach the increase evident in males. Additionally, nadolol and indomethacin reduced the effects of LPS, more so in males. In vivo NKdepletion and ex-vivo NK activity studies suggested that LPS affected LTR through both NKindependent and NK-dependent mechanisms, the latter mediated through prostaglandin release in males. Corticosterone, IL-6, and TNF-α responses to LPS were sexually dimorphic, but were not associated with LPS or drugs' impacts on LTR. Overall, our findings demonstrate sexual dimorphism in LPS-induced elevated susceptibility to MADB106 experimental metastasis, and in potential humoral underlying mechanisms. Further studies are needed to elucidate additional immunological and non-immunological mediators of these dimorphisms, as well as to assess their involvement in other sexually dimorphic pathologies that are associated with inflammation.

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

“…These findings suggest that female F344 rats are more resilient than males to stress-induced NK suppression in general, and specifically to effects mediated through activation of the SNS. These sexual dimorphisms are consistent with our previous studies employing other stress paradigms [48], and specifically with respect to the impact of β-adrenergic receptor activation on NKCC [54, 55]. …”

“…Furthermore, we have shown that several stress paradigms, or the administration of stress-related factors (catecholamines and their agonists, and prostaglandins), can increase LTR in normal F344 rats, but not in NK-depleted rats, indicating that increased LTR in normal rats under these conditions reflects an in vivo suppression of NK-mediated activity [26, 27]. On the other hand, other manipulations, including surgery or LPS administration [40, 48], increased LTR in both normal and NK-depleted rats, indicating the involvement of non-NK mechanisms in modulating LTR. Thus, the use of this LTR index, in conjunction with an NK-depletion paradigm, can indicate the specific in vivo involvement of NK cells in various manipulations that affect LTR.…”

Neonatal immune challenge alters reproductive development in the female rat

“…In addition to the role played by gonadotrophin-releasing hormones (GnRH) and gonadal steroids in sexual differentiation and reproduction, sex hormones are also involved in immune system modulation and development (Tanriverdi et al, 2003;Verthelyi, 2001), as well as playing an important role in brain ontogeny (Harris, 1964). Sexual dimorphism in immune and neuroendocrine responses, driven by reproductive hormonal fluctuations, has been investigated in a number of human and animal studies (Grossman, 1985;Naor et al, 2009). Oestrogen has been shown to attenuate, and testosterone to exacerbate, inflammatory responses in rats (Razmara et al, 2005).…”

Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period

“…These findings indicate the involvement of SNS and HPA reactivity in regulating the immunostimulatory effect of CpG-C through the systemic release of CAs and GCs. Stress responses are common in response to several immune-stimulatory agents (e.g., LPS [22]) and in natural responses to pathogens [46], and could constitute a self-limiting mechanism of TLR-9 activation by CpG-C. Interestingly, with respect to CpG-C, we were unable to observe systemic elevated levels of CORT at the time points studied herein and in previous studies in mice [5, 47]. Nevertheless, in vitro physiological CORT levels dose-dependently reduced the efficacy of CpG-C in elevating IL-12 levels.…”

“…Opioids were also implicated in immune modulation and were shown to inhibit cellular and humoral immunity, including cytokine production and NK cell activity [21]. It is worthy to note that various types of immune stimulation (BRMs) were reported to induce stress responses, including activation of the SNS and HPA axis [22], which could constitute a negative feedback loop.…”