Matthew J. Kluger

Effect of nicotine on the immune system: Possible regulation of immune responses by central and peripheral mechanisms

Nicotine (NT) treatment impairs T-cell receptor (TCR)-mediated signaling, leading to the arrest of T cells in the G1 phase of the cell cycle and inhibition of the antibody plaque-forming cell (AFC) response to sheep red blood cells (SRBC). This paper summarizes some of the previous findings related to cigarette smoke/NT and the immune response, and presents preliminary evidence suggesting that mice chronically treated with NT (0.5 mg/day/kg body weight) have a depressed inflammatory response in the turpentine-induced abscess model of inflammation. This ability of nicotine to attenuate an inflammatory response may also be the cause of reduced mortality of chronically nicotine-treated mice from acute influenza A pneumonitis. Moreover, in LEW rats, decreased anti-SRBC AFC responses were also observed after intracerebroventricular (i.c.v.) administration of relatively small concentrations of NT (28 micrograms/day/kg body weight) which, when given peripherally, did not affect the AFC response. In vitro the addition of NT to T cells increased protein tyrosine kinase (PTK) activity and intracellular Ca2+ concentration [Ca2+]i. These results support the hypothesis that NT alters immune responses by directly interacting with T cells, as well as indirectly through brain-immune interactions.

An antipyretic role for interleukin-10 in LPS fever in mice

Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1β, IL-6, and tumor necrosis factor (TNF)-α. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 μg/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 μg/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-α, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fishers exact test, P < 0.05). Fever in response to the injection of turpentine (100 μl/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 microgram/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 microgram/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-alpha, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fishers exact test, P < 0.05). Fever in response to the injection of turpentine (100 microliter/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.

Nicotine-Induced Modulation of T Cell Function

Tobacco smoking may predispose humans to respiratory disease, and may be a compounding risk factor in HIV infection and progression to AIDS. We have demonstrated that chronic exposure of mice and rats to cigarette smoke or nicotine inhibits T cell responsiveness, which may account for the decreased antibody response to T-dependent antigens seen in these animals. This inhibition may result from aberrant antigen-mediated signaling and depletion of IP3-sensitive Ca2+ stores in nicotine-treated animals. Moreover, nicotine appears to moderate the inflammation associated with turpentine-induced sterile abscess and influenza infection. These anti-inflammatory properties of nicotine may account for longer survival of nicotine-treated than control mice lethally infected with influenza virus. However, because inflammation is required for clearance of many pathogens, nicotine-treated mice exhibit significantly higher titers of influenza virus following infection. These results offer an explanation for the higher susceptibility to some infectious diseases, but greater resistance to some inflammatory diseases among human smokers.

THE USE OF KNOCKOUT MICE TO UNDERSTAND THE ROLE OF CYTOKINES IN FEVER

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques.

Chapter 22 Fever and antipyresis

Publisher Summary This chapter reviews the role of endogenous pyrogens and endogenous cryogens in the regulation of body temperature during fever. Fevers are triggered by the release of endogenous pyrogens from a large number of different types of macrophage-like cells. These endogenous pyrogens include the cytokines interleukin-1 (IL- 1), IL-6, and others. In addition to the release of endogenous pyrogens, there are also endogenous antipyretics or cryogens, which act to modulate the febrile rise in body temperature, thus generally preventing the body temperature from rising to the dangerous levels. Over the past few years, investigators have shown that arginine vasopressin, α -melanocyte stimulating hormone, glucocorticoids, and, in some cases, tumor necrosis factor (TNF α ) may act as endogenous antipyretics. This highly regulated nature of fever, containing factors that raise body temperature and others that prevent this rise in body temperature from becoming too high, supports the hypothesis that fever has evolved as a beneficial host defence response. There are considerable data supporting the hypothesis that cytokines are responsible for the fever associated with infection and cancer.

Endotoxin Tolerance Does Not Alter Open Field-Induced Fever in Rats

Exposure to an open field has been shown to cause a rise in the body temperature of rats. In many respects, this rise in body temperature is similar to fevers caused by endotoxin and other inflammatory stimuli. Rats repeatedly injected with endotoxin develop tolerance to the fever-inducing action of endotoxin. We hypothesized that repeated pretreatment with endotoxin would modify the fever caused by exposure to psychological stress. To test this hypothesis, we compared open field-induced fevers in rats made endotoxin tolerant to those rats not endotoxin tolerant. We found that endotoxin tolerance had no effect on open field fevers.

β-Adrenergic Receptor Subtype Effects on Stress Fever and Thermoregulation

Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or ‘open field.’ The β-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these β-antagonists discriminates between subtypes of β-receptors. The purpose of this study was to determine the relative contribution of the different β-receptor types to stress fever using β1-, β2-, and β3-receptor subtype selective antagonists (atenolol [β1], ICI-118551 [β2], and SR 59230A [β3]) and agonists (dobutamine [β1], salbutamol [β2], and BRL 37344 [β3]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system β-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the β3-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective β2-agonist, salbutamol, and the β3-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by β-blockers may be due to the sedative actions of these drugs.

Cytokine Actions on Fever

Contact with pathogens or simply tissue injury (e.g., sterile abscess) causes the release of cytokines from different cells within the body. Proinflammatory cytokines (e.g., interleukin-1 [IL-1] and IL-6) cause the thermoregulatory set-point to rise at the hypothalamus, and body temperature increases as the result of a coordinated series of physiological and behavioral responses. In humans, fever is accompanied by physiological responses (e.g., peripheral vasoconstriction and shivering) and behavioral responses (e.g., curling into a fetal position, wearing additional clothing and soaking in a warm bath).

Hemorrhage Suppresses Fever, lnterleukin-6, and Tumor Necrosis Factor-αResponses to Lipopolysaccharide in Rats

The purpose of this study was to test the hypothesis that attenuation of the fever response to lipopolysaccharide (LPS) following hemorrhage is accompanied by changes in serum glucocorticoid levels and a decreased bioactivity of TNF-alpha and IL-6 in plasma. Hemorrhage was induced in rats by the withdrawal of 20% of estimated total blood volume. LPS (50 microg/kg) or saline were injected intraperitoneally immediately after the hemorrhage. Blood samples were taken 1.5 h for TNF-alpha bioactivity and corticosterone measurements and 5 h after treatment for IL-6 bioactivity. Body temperature (Tb) was measured by biotelemetry. The 20% hemorrhage led to a significant reduction in hematocrit measured at 1.5 and 5 h after treatment. Furthermore, 20% hemorrhage caused a substantial elevation in serum corticosterone measured by radioimmunoassay at 1.5 h after treatment. This high concentration of corticosterone was not further potentiated by injection of LPS. Hemorrhaged rats treated with LPS responded with a markedly attenuated fever. Both TNF-alpha and IL-6 rises in the circulation due to LPS injection were significantly smaller in hemorrhaged rats compared to nonhemorrhaged LPS-injected rats. However, this degree of hemorrhage did not alter the T(b) or plasma TNF-alpha and IL-6 activity in hemorrhaged rats injected with saline. These results show that the inhibitory effect of hemorrhage on LPS-induced fever may be related to the decreased TNF-alpha and IL-6 activity in plasma. Hemorrhage-induced high level of corticosterone might contribute to the attenuation of fever, perhaps via the suppression of pyrogenic cytokines.