Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor

Surgery is imperative for cancer treatment, but was suggested to suppress immunity and facilitate metastasis. Here we study the involvement of catecholamines and prostaglandins (PG) in such outcomes, and the role played by marginating-pulmonary (MP)-NK cells in controlling MADB106 metastasis. Non-operated and laparotomized F344 rats were injected postoperatively with a PG synthesis inhibitor (indomethacin, 4 mg/kg i.p.), a beta-blocker (nadolol, 0.6 mg/kg s.c.), both drugs, or vehicle. Rats were then inoculated intravenously with non-immunogenic syngeneic MADB106 cells, and 24 h later lung tumor retention was assessed, or 3 weeks later lung metastases were counted. Additionally, 12 h after surgery we harvested MP-NK cells and circulating-NK cells and compared their numbers and cytotoxicity against MADB106 cells and standard YAC-1 target cells. Surgery significantly increased MADB106 metastasis. Nadolol and indomethacin reduced this effect by approximately 50% when used alone, and significantly more (75%) when used together. Only MP-leukocytes exhibited NK cytotoxicity against MADB106 cells. Surgery markedly suppressed it, and nadolol and indomethacin additively restored it. Similar effects were observed assessing MP-NK and circulating-NK cytotoxicity against YAC-1 target cells. Alterations in the numbers of NK cells were partly associated with alterations in total MP-NK activity, but not with circulating-NK activity. Last, administrating nai ve rats with physiologically relevant doses of a beta-adrenergic agonist (metaproterenol), and/or with PGE2, additively and independently of each other promoted MADB106 metastasis, simulating the effects of surgery. These findings point at potential prophylactic measures in cancer patients undergoing surgery, and suggest a role for MP-NK cells in resisting metastasis of apparently insensitive tumors.     

Synergism between immunostimulation and prevention of surgery-induced immune suppression: An approach to reduce post-operative tumor progression

Background: A unique opportunity to eradicate cancer is presented immediately after the excision of the primary tumor, but surgical procedures often induce the release of immunosuppressing factors that render cell mediated immunity ineffective. Here we tested the hypothesis that integration of peri-operative immunostimulation and blockade of immunosuppression could synergistically improve post-operative anti-metastatic immunity and long-term survival. Methods: Two syngeneic tumor models in F344 rats were employed, studying post-operative tumor progression. In the first model, survival following laparotomy and CRNK-16 leukemia was studied. Rats were peri-operatively treated with the immuno-stimulant poly I-C (5 × 0.2 mg/kg/inj), with catecholamine- and prostaglandin-blockers (shown to prevent post-operative immunosuppression: 4.5 mg/kg nadolol, 4 mg/kg indomethacin), with both interventions, or with neither. Long-term survival was assessed thereafter. The second model used the MADB106 mammary adenocarcinoma, assessing its lung tumor retention (LTR) following i.v. inoculation, as well as host marginating-pulmonary NK numbers and activity against this tumor. IL-12 was employed for immunostimulation (4 × 1.5 μg/kg/inj), with and without the above blockers. Results: Post-operative CRNK-16 survival rates were significantly improved only by the integrated approach of immune stimulation and endocrine blockers. Post-operative MADB106 LTR was additively reduced by the two interventions. Importantly, while IL-12 increased pulmonary NK cytotoxicity against MADB106, surgery markedly suppressed this cytotoxicity in both IL-12 and vehicle treated animals. The blockers prevented this suppression per lung and per single NK cell. Conclusions: Immunostimulation could be rendered ineffective post-operatively due to immunosuppression; therefore integrating endocrine-blocker therapies into the realm of peri-operative immunotherapy could optimize immune control over residual disease, potentially improving clinical outcomes.     

Intracerebral interleukin-1β impairs response to tumor invasion: involvement of adrenal catecholamines

Interleukin-1β (IL-1β) is released within the brain following stress, trauma, infection, and in specific brain disorders. This centrally acting IL-1β has recently been shown to impair peripheral immunity. Central administration of IL-1β suppresses natural killer (NK) cell activity impairs lung clearance of tumor cells and enhances tumor colonization. Using an in vivo model of tumor colonization (lung clearance of NK-sensitive MADB106 adenocarcinoma cells), this study examined the role of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) in mediating these effects. We demonstrate that adrenalectomy significantly attenuated the impaired lung clearance of MADB106 tumor cells induced by intracerebroventricular (i.c.v.) administration of IL-1β (20 ng). Supplementing adrenalectomized animals with corticosterone did not reinstate the effect. The effect of IL-1β on lung clearance was blocked by pretreatment with the β-adrenergic antagonist, nadolol (0.5 mg/kg), but not by the α-antagonist phentolamine (5 mg/kg). Peripheral noradrenergic pathways are not implicated given that systemic administration of the noradrenergic neurotoxin, 6-hydroxydopamine, did not block the effect of IL-1β. Taken together, these findings indicate that IL-1β impairs lung clearance of MADB106 tumor cells via the actions of adrenal catecholamines, most likely epinephrine, acting at β-adrenergic receptors in the periphery.     

Male--female differences in the impact of beta-adrenoceptor stimulation on resistance to experimental metastasis: exploring the effects of age and gonadal hormone involvement

We studied the development of sexual dimorphism in resistance to NK-sensitive experimental metastasis under baseline conditions and following adrenoceptor stimulation. With increasing age, baseline resistance to MADB106 lung tumor retention (LTR) increased in both sexes, but also the susceptibility to the tumor-enhancing effects of a beta-adrenergic agonist, metaproterenol. Beginning at 13 weeks, males exhibited a 2- to 3-fold greater increase in LTR than females following adrenoceptor stimulation. This adult dimorphism was robust to ovariectomy, and questionably related to androgens. The findings are consistent with reduced female responsiveness to sympathetic activation, and substantiate the importance of including both sexes when studying neuroimmunomodulation.     

Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study

OBJECTIVES: Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats. METHODS: Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection. RESULTS: At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner. CONCLUSION: These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.     

Natural killer cell activity and resistance to tumor metastasis in prepubescent rats: deficient baselines, but invulnerability to stress and beta-adrenergic stimulation

Although young children and animals exhibit high rates of tumor development, little is known about natural killer (NK) cell activity in the very young. We recently provided direct evidence that reduced levels of NK activity in prepubescent rats underlie higher levels of susceptibility to metastasis. The aim of the current study was to further characterize NK activity and tumor resistance in prepubescent rats, specifically with respect to the effects of stress and sex, as these factors have been shown to modulate tumor development in adult populations. Two NK outcomes were assessed: levels of whole blood NK cytotoxicity and lung tumor retention of NK-sensitive MADB106 tumor cells which metastasize only to the lungs. The corticosterone (CS) response to surgery was also assessed. In the first set of experiments, prepubescent males and females (36 days of age) and mature males (98 days) were subjected to abdominal surgery and 5 h later were either tested for plasma CS levels or challenged with MADB106 tumor cells. The findings indicated that whereas surgery increased CS levels in the young rats to similar levels observed in mature animals, surgical stress did not increase lung tumor retention in the young animals, despite exerting marked and significant effects in the mature rats. These findings persisted when lower tumor loads were used in the young rats to compensate for the markedly reduced resistance to metastasis in this population. Because surgery involves activation of the sympathetic nervous system (SNS) which is known to regulate NK activity, we assessed the impact of the beta-adrenergic agonist, metaproterenol, on NK activity and on lung tumor retention. Metaproterenol (0.8 mg/kg, 1 h before testing) resulted in a large suppression of NK activity and resistance against MADB106 metastasis in mature males and females, but not in prepubescent animals. In mature, but not in young animals, males exhibited higher baseline levels of NK activity. Taken together, these findings indicate that NK cells of prepubescent rats are resistant to beta-adrenergic stimulation, and suggest that prepubescent rats are markedly less responsive to SNS-induced suppression of NK activity, which may underlie their invulnerability to the effects of surgery on MADB106 metastasis.     

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

We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed – both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and β-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.     

Fetal testosterone influences sexually dimorphic gray matter in the human brain

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.     

Sexual dimorphism in the pituitary-adrenal response to tumor necrosis factor-alpha, but not to interleukin-6, in the rat

It is known that the pituitary-adrenal responses to lipopolysaccharide and interleukin (IL)-1 are sexually dimorphic in rodents, with females having an enhanced secretion of adrenocorticotropin (ACTH) and corticosterone. This study investigated whether the ACTH and corticosterone responses to tumor necrosis factor (TNF)-alpha and IL-6, two principal proinflammatory cytokines, are also modulated by the sex steroid milieu in the rat. Mature male and female rats received an intravenous administration of TNF-alpha(10 microg/kg) and IL-6 (10 microg/kg), and changes in plasma ACTH and corticosterone levels were determined over time. The effect of gonadectomy on the hormonal responses was also examined in both sexes. TNF-alpha induced significantly higher responses of ACTH and corticosterone in females than in males, and this sexual difference was abolished by gonadectomy in both sexes. By contrast, the hormonal responses to IL-6 were not significantly affected by either gender or gonadectomy. These results suggest a sex steroid-dependent modulation of the TNF-alpha-induced, but not the IL-6-induced, ACTH and corticosterone secretion in the rat. Further evidence for the sexually dimorphic neuroimmunoendocrine activity is reported herein.     

Prenatal flutamide alters sexually dimorphic nuclei in the spinal cord of male rats.

The effects of prenatal exposure to the antiandrogen flutamide on two sexually dimorphic nuclei of the lumbar spinal cord, the dorsolateral nucleus (DLN) and the spinal nucleus of the bulbocavernosus (SNB), were investigated. Rat dams were given daily injections of 5 mg flutamide or vehicle alone from day 11 through 21 of pregnancy. The spinal cords and perineal morphology of their male and female offspring were examined in adulthood. Flutamide reduced the number of SNB and DLN neurons, reduced the somal and nuclear area of SNB neurons, and reduced the weight of the perineal muscles in males. Flutamide produced no effect in females. No sexual dimorphism was found in the mean somal area of DLN neurons, but a sexual dimorphism was found in the distribution of somal areas in our samples; females had proportionately more large neurons than males. Flutamide-treated males also had proportionately more large neurons than control males but fewer than females. A sexual dimorphism was found in the nuclear areas of DLN neurons but flutamide did not influence this trait.     

Development of the sexually dimorphic nucleus of the preoptic area and the influence of estrogen-like compounds

One of the wel -defined sexual y dimorphic structures in the brain is the sexual y dimorphic nucleus, a cluster of cells located in the preoptic area of the hypothalamus. The rodent sexual y dimorphic ...     

Buprenorphine ameliorates the effect of surgery on hypothalamus-pituitary-adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment

Not all opioids employed in clinical practice share the same immunosuppressive properties. The potent partial micro-agonist buprenorphine appears to exhibit a neutral effect on the immune responses. Surgery stress is associated with decreased natural killer cell activity (NK) and enhancement of tumor metastasis in rats. We analyzed the ability of buprenorphine to prevent the effects of experimental surgery on HPA activation (plasma corticosterone levels), NK activity and lung diffusion of the NK sensitive tumor MADB106. Buprenorphine (0.1mg/kg) was compared with equianalgesic doses of fentanyl (0.1mg/kg) and morphine (10mg/kg) in this animal model. In normal animals morphine and fentanyl stimulate the HPA axis, decrease NK activity and augment tumor metastasis, while buprenorphine is devoid of these effects. Surgery significantly raised corticosterone levels, suppressed NK activity and increased MADB106 metastasis. Only buprenorphine was able to prevent the neuroendocrine and immune system alterations and ameliorate the increase of tumor metastasis induced by surgical stress. These preclinical findings suggest that an adequate treatment of surgically induced stress immunosuppression with an opioid drug devoid of immunosuppressive effects may also play a protective role against the metastatic diffusion following cancer surgery.     

Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells

Surgery stress has been shown to be associated in rat with decreased natural killer (NK) cell activity and enhancement of tumor metastasis. We have previously shown that the analgesic drug tramadol stimulates NK activity both in the rodent and in the human. In the present study, we analyze, in the rat, tramadol ability to prevent the effect of experimental surgery on NK activity and on the enhancement of metastatic diffusion to the lung of the NK sensitive tumor model MADB106. The administration of tramadol (20 and 40 mg/kg) before and after laparatomy significantly blocked the enhancement of lung metastasis induced by surgery. In contrast, the administration of 10 mg/kg of morphine was not able to modify this enhancement. The modulation of NK activity seemed to play a central role in the effect of tramadol on MADB106 cells. In fact, both doses of tramadol were able to prevent surgery-induced NK activity suppression, while the drug significantly increased NK activity in normal non-operated animals. Morphine, that in normal rats significantly decreased NK cytotoxicity, did not prevent surgery-induced immunosuppression. The good analgesic efficacy of tramadol combined with its intrinsic immunostimulatory properties suggests that this analgesic drug can be particularly indicated in the control of peri-operative pain in cancer patients.     

Ethanol increases tumor progression in rats: possible involvement of natural killer cells.

The effects of acute and chronic ethanol administration on tumor progression and metastasis were studied in rat models of leukemia and breast cancer, respectively. Acute administration of 1.5-3.5 g of ethanol/kg body weight significantly reduced survival of rats injected with CRNK-16 leukemia cells in a dose-related manner. Acute administration of 2.5-3.5 g of ethanol/kg body weight, one hour before tumor inoculation, or chronic consumption of liquid diet containing ethanol for two weeks before and three weeks after tumor inoculation, significantly increased the number of lung metastases of MADB106 mammary adenocarcinoma. The ethanol-induced increase in the number of metastases was not correlated with plasma levels of corticosterone and was not altered by the opiate antagonist naltrexone. Incubation of spleen cells in vitro in the presence of ethanol, at concentrations comparable to those measured in the blood of ethanol-treated rats, significantly suppressed natural killer (NK) cell activity against MADB106 cells in a standard chromium-release assay and decreased the binding of effector to MADB106 tumor cells. However, neither acute nor chronic ethanol administration in vivo altered splenic NK activity against this tumor in the same in vitro assay, in which the ethanol would have been washed away. These results suggest that, in the presence of ethanol, tumor progression is facilitated. The possibility that this facilitation is related to ethanol-induced impairment of the normal tumoricidal interaction between NK and tumor cells is discussed.     

Continuous stress disrupts immunostimulatory effects of IL-12

Immune stimulation by biological response modifiers is a common approach in tumor immunotherapy. IL-12 was found effective in various animal studies, but clinical trials showed limited success. However, among other differences, animal models do not simulate psychological or physiological stress while employing IL-12, whereas cancer patients often experience distress while treated with immunostimulants. Thus, in the current study we assessed the impact of continuous stress on the efficacy of IL-12 immunostimulation. F344 rats were subjected to a pharmacological stress paradigm (continuous administration of a β-adrenergic agonist) or to a 20 h behavioral stress paradigm (wet cage exposure) commencing 2 h before IL-12 administration. Twenty-six hours after stress initiation, we studied indices known to reflect IL-12 immunostimulatory impacts, including NK cell numbers and activity in different immune compartments, and in vivo resistance to MADB106 lung tumor colonization. The results indicated that both the pharmacological and behavioral stress paradigms significantly reduced the increase in the number and activity of marginating-pulmonary NK cells evident in non-stressed IL-12 treated animals. Additionally, stressed animals exhibited a lower IL-12-induced improvement of MADB106 lung clearance, an in vivo index that markedly depends on total marginating-pulmonary NK activity. These deleterious effects of stress were more prominent in males than in females. Overall, the findings demonstrate that prolonged stress exposure can disrupt the efficacy of simultaneous immunostimulatory treatments, irrespective of stress effects on baseline immune measures. Neuroendocrine and cellular mediating mechanisms are yet unknown, but the potential clinical ramifications of these findings warrant consideration in clinical trials employing immunostimulatory agents.     

Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and beta(1)- and beta(2)-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective beta-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective beta(1)- (atenolol, 1-6 mg/kg) and a selective beta(2)-antagonist (either butoxamine 4-32 mg/kg or ICI-118,551 0.3-8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1-1 mg/kg) or of a beta-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating beta(1)- and beta(2)-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.     

Sex difference in the bed nucleus of the stria terminalis of the human brain.

A quantitative analysis of the volume of the darkly staining region of the posteromedial bed nucleus of the stria terminalis was performed on the brains of 26 age-matched male and female human subjects. We suggest the term "darkly staining posteromedial" component of the bed nucleus of the stria terminalis (BNST-dspm) to describe this sexually dimorphic region of the human brain. The volume of the BNST-dspm was 2.47 times greater in males than in females. This region in humans appears to correspond to an area of the bed nucleus of the stria terminalis in laboratory animals that exhibits volumetric and neurochemical sexual dimorphisms, concentrates gonadal steroids, and is anatomically connected to several other sexually dimorphic nuclei. Furthermore, the bed nucleus of the stria terminalis is involved in sexually dimorphic functions, including aggressive behavior, sexual behavior, and gonadotropin secretion, which are also influenced by gonadal steroids. Therefore, it is possible that in human beings as well, gonadal hormones influence the sexual dimorphism in the BNST-dspm and that this morphological difference, in part, underlies sexually dimorphic function.     

Inducing a mode of NK-resistance to suppression by stress and surgery: a potential approach based on low dose of poly I-C to reduce postoperative cancer metastasis

Perioperative suppression of NK activity has been suggested to compromise host resistance to tumor progression. Here, we sought to develop a clinically applicable preoperative regimen to prevent immunosuppression and promotion of metastasis by stress or surgery. The synthetic ds-RNA, poly I-C, was used in vivo in F344 rats, based on its alleged in vitro ability to protect immunocytes from suppression by cAMP elevating agents. Different regimens of poly I-C were studied in controls and in rats subjected to a pharmacological stressor, swim stress, or surgical stress. Resistance to lung experimental metastasis of the syngeneic non-immunogenic MADB106 mammary adenocarcinoma was assessed. Numbers of circulating and marginating-pulmonary NK cells and their cytotoxicity against the MADB106 and YAC-1 target lines were also studied. Our findings established a regimen of repeated low-dose poly I-C administration with minimal side effects (0.2mg/kg i.p. 5, 3, and 1day before tumor inoculation). This regimen, while hardly affecting resistance levels in non-stressed animals, prevented all stressors from promoting metastases. These beneficial effects occurred in the presence of a primary tumor and in both sexes. Poly I-C increased the numbers of NK cells, and, on a per NK cell basis, while not increasing cytotoxicity, profoundly protected marginating-pulmonary NK cells from suppression by surgery. This study suggests a non-toxic clinically translatable prophylactic use of poly I-C to target the critical perioperative period. By increasing the number of marginating-pulmonary NK cells, and by transforming them into a mode of resistance to immunosuppression, this approach may reduce postoperative metastasis in cancer patients.     

Sexual dimorphism in the bed nucleus of the accessory olfactory tract in the rat

This work investigates the existence of sex differences in the volume and number of neurons and glial cells in the bed nucleus of the accessory olfactory tract (BAOT). Males showed larger volume and number of cells than female rats. Early postnatal (day 1 after birth) orchidectomy in males, and androgenization in females, reversed these differences. No sex differences were found in BAOT glial cells. The sexual dimorphism found in the neuron/glial cell ratio reflects sex differences in neuron number. The existence of sexual dimorphism in the BAOT supports our earlier hypothesis which states that the vomeronasal system (VNS) is sexually dimorphic.     

beta(2)-Adrenergic receptor-dependent sexual dimorphism for murine leukocyte migration

In wild-type FVB mice, leukocyte recruitment to lipopolysaccharide was sexually dimorphic, with a greater number of leukocytes recruited in females. In male beta(2)-adrenergic receptor knock out mice (bred on a congenic FVB background) the number of leukocytes recruited was increased approximately 4-fold, while in females there was no change, eliminating sexual dimorphism in leukocyte migration. While there were significantly fewer recruited CD62L(+) and CD11a(+) leukocytes in wild-type males, only in male beta-adrenergic receptor knock out mice was there an increase in the number of recruited CD11a(+) leukocytes, again eliminating sexual dimorphism. Thus, leukocyte migration and CD11a(+) adhesion molecule expression in male, but not in female, leukocytes is beta-adrenergic receptor-dependent. Our findings provide support for a role of beta(2)-adrenergic receptor mechanisms in the inflammatory response, and suggest that beta(2)-adrenergic receptor on male leukocytes contributes to sexual dimorphism in the effect of stress on inflammatory diseases.