Central administration of rat IL-6 induces HPA  activation and fever but not sickness behavior in rats

Lenczowski, M. J. P.; Bluthé, Rose Marie; Roth, Joachim; Rees, Gwen S.; Rushforth, David; Dam, Anne Marie Van; Tilders, F. J. H.; Dantzer, Robert; Rothwell, Nancy J.; Luheshi, Giamal N.

doi:10.1152/ajpregu.1999.276.3.r652

Cited by 79 publications

(78 citation statements)

References 34 publications

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“…23,38,59 Interestingly, however, one study reported that administration of IL-6 only reduced locomotor activity in the presence of IL-1-beta, while having no effects on it own. 60 Taken together with the results from our study (where TNF-R1-KO animals exhibited unchanged CNS IL-beta responses), these data raise the possibility that additional pathways (such as IL-1) associated with IL-6 (but not primarily involving TNF-alpha) may be responsible for altered locomotor activity in virally infected mice. Indeed, as noted above, IL-1 has been shown to reduce locomotor activity both alone and in combination with IL-6.…”

Section: Discussionsupporting

confidence: 74%

“…Indeed, as noted above, IL-1 has been shown to reduce locomotor activity both alone and in combination with IL-6. [40][41][42]60 Given the critical role played by glucocorticoids in regulating immune responses (especially restraining inflammatory responses), patient populations with altered glucocorticoid signaling as result of reduced hormone or reduced glucocorticoid receptor expression/function, including post-traumatic stress disorder (PTSD) and major depression, may be especially vulnerable to the pathological/behavioral consequences of prolonged exposure to elevated circulating levels of proinflammatory cytokines. Indeed, both of these disorders have been found to be associated with an exaggerated inflammatory responses including increases in plasma concentrations of TNF-alpha and IL-6, and both are associated with increased symptoms of anxiety and alterations in locomotor activity, including psychomotor slowing and fatigue.…”

Section: Discussionmentioning

confidence: 99%

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Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Silverman

MacDougall

et al. 2006

Mol Psychiatry

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Endogenous glucocorticoids restrain proinflammatory cytokine responses to immune challenges such as viral infection. In addition, proinflammatory cytokines induce behavioral alterations including changes in locomotor/exploratory activity. Accordingly, we examined proinflammatory cytokines and open-field behavior in virally infected mice rendered glucocorticoid deficient by adrenalectomy (ADX). Mice were infected with murine cytomegalovirus (MCMV), and open-field behavior (36 h post-infection) and plasma concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 (42 h post-infection) were assessed. Compared to sham-ADX-MCMV-infected animals, ADX-MCMV-infected mice exhibited significant reductions in total distance moved, number of center entries, and time spent in center. These behavioral alterations were accompanied by significantly higher plasma concentrations of TNF-alpha and IL-6, both of which were correlated with degree of behavioral change. To examine the role of TNF-alpha in these behavioral alterations, open-field behavior was compared in wild-type (WT) and TNF-R1-knockout (KO), ADX-MCMV-infected mice. TNF-R1-KO mice exhibited significantly attenuated decreases in number of rearings, number of center entries and time spent in center, but not distance moved, which correlated with plasma IL-6. Given the potential role of brain cytokines in these findings, mRNA expression of TNF-alpha, IL-1 and IL-6 was assessed in various brain regions. Although MCMV induced increases in proinflammatory cytokine mRNA throughout the brain (especially in ADX animals), no remarkable differences were found between WT and TNF-R1-KO mice. These results demonstrate that endogenous glucocorticoids restrain proinflammatory cytokine responses to viral infection and their impact on locomotor/exploratory activity. Moreover, TNF-alpha appears to mediate cytokine-induced changes in open-field behaviors, especially those believed to reflect anxiety.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Silverman

MacDougall

et al. 2006

Mol Psychiatry

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“…Also, mice infected with Ad5mIL6 adenovirus (known to induce excessive IL-6 concentrations over several days) decreased food, water and sucrose intake, novel object exploration, and swimming in the forced swim test [62]. On the other hand, Lenczowski et al [43] reported that i.c.v. IL-6 did not result in changes in social investigatory and locomotor behavior; it reduced the behaviors only when it was administered along with IL-1.…”

Section: Introductionmentioning

confidence: 99%

Feeding, exploratory, anxiety- and depression-related behaviors are not altered in interleukin-6-deficient male mice

Świergiel

Dunn

2006

Behavioural Brain Research

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Interleukin-6 (IL-6) has been implicated in behavioral responses associated with inflammation, sickness behavior and various nervous system disorders. We studied a range of different behaviors in IL-6-knockout (IL-6ko) and wild-type (WT) male mice. No significant differences were observed in ambulatory, exploratory, and stereotypic activities in home or novel cages, in an open field (OF), in the multicompartment chamber (MCC), or in the elevated plus-maze (EPM). IL-6ko mice shed fewer fecal boli than WT mice in the OF, in novel cages and in the MCC although this effect was not statistically significant in the OF. In novel cages, intraperitoneal (i.p.) injection of IL-6 (1 μg) depressed ambulatory activity slightly more in IL-6ko than in WT mice. Restraint and interleukin-1β (IL-1β, 100 ng i.p.) decreased exploration of mice in the MCC and EPM, but there was no indication of altered sensitivity in IL-6ko mice. No significant differences were detected in the tail suspension and the Porsolt forced swim tests. IL-1β and lipopolysaccharide (LPS 1 μg i.p.) injection depressed sweetened milk and solid food intake similarly in IL-6ko and WT mice, but IL-6 had no effect, suggesting that IL-6 is not involved in these effects of IL-1 or LPS. However, IL-1β and LPS depressed body weight more in WT than in IL-6ko mice. Plasma corticosterone and basal concentrations of catecholamines, indoleamines and their metabolites in several brain regions were similar. The responses in these measures to IL-1β and LPS were also similar, except that there were no significant changes in tryptophan and serotonin metabolism in IL-6ko mice. This may reflect a role for IL-6 in the tryptophan and serotonin responses to IL-1 and LPS. It is concluded that the lack of IL-6 is not associated with substantial alterations in several different mouse behaviors, and in the responses to restraint, IL-1β, IL-6 and LPS.

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“…A large amount of evidence identifies IL-6 as a necessary factor for the fever response even though IL-6 by itself is not or only weakly or moderately pyrogenic (Cao et al, 2001;Cartmell et al, 2000;Chai et al, 1996;Harden et al, 2008;Kozak et al, 1998;LeMay et al, 1990;Lenczowski et al, 1999;Nilsberth et al, 2009a;Rummel et al, 2006). However, the origin of IL-6 in immune-induced fever has not been fully identified, although there are reports showing that IL-6 can be produced by a variety of cells in response to different pathological stimuli.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

Hamzic

Tang

Eskilsson

et al. 2013

Brain, Behavior, and Immunity

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KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.Hamzic et al., page 3

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Central administration of rat IL-6 induces HPA activation and fever but not sickness behavior in rats

Cited by 79 publications

References 34 publications

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Feeding, exploratory, anxiety- and depression-related behaviors are not altered in interleukin-6-deficient male mice

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

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