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Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Ruzek MC, Miller AH, Opal SM, Pearce BD, Biron CA - J. Exp. Med. (1997)

Bottom Line: Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses.The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses.Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

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Corticosterone levels in mice with neutralized cytokine  function. Corticosterone levels in MCMV-infected (5 × 104 PFU/ mouse) (filled bar) or vehicle-injected (striped bar) IL-6–deficient (IL-6–),  IFN-γ–deficient (IFN-γ−), IL-1ra–treated (IL-1ra) mice or respective  control mice (IL-6+, IFN-γ+, PBS). Treatments were as described in Materials and Methods. Corticosterone levels were measured in serum samples collected from mice under low stress conditions (bled within 4 min  of handling) 36 h after infection. Results from one of two to three experiments are shown. Data are means ± SE of three mice per group. **P  <0.01.
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Figure 3: Corticosterone levels in mice with neutralized cytokine function. Corticosterone levels in MCMV-infected (5 × 104 PFU/ mouse) (filled bar) or vehicle-injected (striped bar) IL-6–deficient (IL-6–), IFN-γ–deficient (IFN-γ−), IL-1ra–treated (IL-1ra) mice or respective control mice (IL-6+, IFN-γ+, PBS). Treatments were as described in Materials and Methods. Corticosterone levels were measured in serum samples collected from mice under low stress conditions (bled within 4 min of handling) 36 h after infection. Results from one of two to three experiments are shown. Data are means ± SE of three mice per group. **P <0.01.

Mentions: To characterize the contribution of early cytokine production to induction of glucocorticoid responses, serum corticosterone levels were examined in mice with specifically neutralized endogenous cytokine functions. Individual cytokine functions were evaluated in mice with targeted disruptions of the IL-6 or IFN-γ genes and in normal mice treated with neutralizing anti–IFN-γ antibodies or IL-1 receptor antagonist (IL-1ra). MCMV-induced corticosterone levels were not modified significantly by the presence or absence of IFN-γ; infected IFN-γ–deficient (Fig. 3) and anti–IFN-γ–treated (data not shown) mice had serum corticosterone values similar to those in respective infected control mice. In contrast, MCMV-infected IL-6–deficient and IL-1ra–treated mice demonstrated dramatically reduced corticosterone levels in comparison to respective infected control mice; serum corticosterone levels were decreased by up to 75% in IL-6–deficient mice and by >50% in IL-1ra– treated mice (Fig. 3). Reductions resulting from IL-6 deficiencies were observed in three independent experiments with each experiment containing three mice/group, and those resulting from blocking IL-1 function were observed in two independent experiments with each containing three mice/group. Statistical significance was increased by combination of results from multiple experiments such that the IL-1ra effects were to P <0.05 and the IL-6 deficiency effects were to P <0.01. The cytokine effects on glucocorticoid induction were not a consequence of changes in response kinetics as, in addition to the shown dramatically reduced glucocorticoid levels at 36 h, MCMV-infected IL-6–deficient mice also lacked induced glucocorticoid levels at 24, 48, and 60 h after infection (data not shown). Thus, blocks in endogenous IL-6 or IL-1 functions dramatically attenuate glucocorticoid responses to MCMV infection.


Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Ruzek MC, Miller AH, Opal SM, Pearce BD, Biron CA - J. Exp. Med. (1997)

Corticosterone levels in mice with neutralized cytokine  function. Corticosterone levels in MCMV-infected (5 × 104 PFU/ mouse) (filled bar) or vehicle-injected (striped bar) IL-6–deficient (IL-6–),  IFN-γ–deficient (IFN-γ−), IL-1ra–treated (IL-1ra) mice or respective  control mice (IL-6+, IFN-γ+, PBS). Treatments were as described in Materials and Methods. Corticosterone levels were measured in serum samples collected from mice under low stress conditions (bled within 4 min  of handling) 36 h after infection. Results from one of two to three experiments are shown. Data are means ± SE of three mice per group. **P  <0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196262&req=5

Figure 3: Corticosterone levels in mice with neutralized cytokine function. Corticosterone levels in MCMV-infected (5 × 104 PFU/ mouse) (filled bar) or vehicle-injected (striped bar) IL-6–deficient (IL-6–), IFN-γ–deficient (IFN-γ−), IL-1ra–treated (IL-1ra) mice or respective control mice (IL-6+, IFN-γ+, PBS). Treatments were as described in Materials and Methods. Corticosterone levels were measured in serum samples collected from mice under low stress conditions (bled within 4 min of handling) 36 h after infection. Results from one of two to three experiments are shown. Data are means ± SE of three mice per group. **P <0.01.
Mentions: To characterize the contribution of early cytokine production to induction of glucocorticoid responses, serum corticosterone levels were examined in mice with specifically neutralized endogenous cytokine functions. Individual cytokine functions were evaluated in mice with targeted disruptions of the IL-6 or IFN-γ genes and in normal mice treated with neutralizing anti–IFN-γ antibodies or IL-1 receptor antagonist (IL-1ra). MCMV-induced corticosterone levels were not modified significantly by the presence or absence of IFN-γ; infected IFN-γ–deficient (Fig. 3) and anti–IFN-γ–treated (data not shown) mice had serum corticosterone values similar to those in respective infected control mice. In contrast, MCMV-infected IL-6–deficient and IL-1ra–treated mice demonstrated dramatically reduced corticosterone levels in comparison to respective infected control mice; serum corticosterone levels were decreased by up to 75% in IL-6–deficient mice and by >50% in IL-1ra– treated mice (Fig. 3). Reductions resulting from IL-6 deficiencies were observed in three independent experiments with each experiment containing three mice/group, and those resulting from blocking IL-1 function were observed in two independent experiments with each containing three mice/group. Statistical significance was increased by combination of results from multiple experiments such that the IL-1ra effects were to P <0.05 and the IL-6 deficiency effects were to P <0.01. The cytokine effects on glucocorticoid induction were not a consequence of changes in response kinetics as, in addition to the shown dramatically reduced glucocorticoid levels at 36 h, MCMV-infected IL-6–deficient mice also lacked induced glucocorticoid levels at 24, 48, and 60 h after infection (data not shown). Thus, blocks in endogenous IL-6 or IL-1 functions dramatically attenuate glucocorticoid responses to MCMV infection.

Bottom Line: Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses.The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses.Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Show MeSH
Related in: MedlinePlus