Limits...
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.

Show MeSH

Related in: MedlinePlus

Model for microbial stimulation of glucocorticoid induction.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196262&req=5

Figure 5: Model for microbial stimulation of glucocorticoid induction.

Mentions: Although the glucocorticoid response dependency on IL-1α-induced IL-6 is consistent with results from administering cytokines, the IL-6 requirement in response to challenge with particular agents appears to be specific to viral infections. Two additional systems have not found IL-6 essential for glucocorticoid induction; these are turpentine and LPS challenges (13). IL-1β is readily detectable after injection of LPS (6), however, it is undetectable in serum from MCMV-infected mice. Therefore, during viral infection, the cytokines leading to glucocorticoid production may be more dependent upon an IL-1α to IL-6 cascade, whereas LPS and/or turpentine may induce other cytokines, including IL-1β, that either alone or in combination induce glucocorticoids independently of IL-6 (3). The poly I:C–induced responses also appear to occur under conditions of minimal IL-1β expression. Thus, the ability to define the IL-1α to IL-6 pathway for glucocorticoid induction, in response to MCMV and/or poly I:C, is most likely possible because of the absence of parallel or overlapping pathways for induction. A model for pathways of glucocorticoid induction, after viral as compared to bacterial stimulation, is presented in Fig. 5.


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)

Model for microbial stimulation of glucocorticoid induction.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196262&req=5

Figure 5: Model for microbial stimulation of glucocorticoid induction.
Mentions: Although the glucocorticoid response dependency on IL-1α-induced IL-6 is consistent with results from administering cytokines, the IL-6 requirement in response to challenge with particular agents appears to be specific to viral infections. Two additional systems have not found IL-6 essential for glucocorticoid induction; these are turpentine and LPS challenges (13). IL-1β is readily detectable after injection of LPS (6), however, it is undetectable in serum from MCMV-infected mice. Therefore, during viral infection, the cytokines leading to glucocorticoid production may be more dependent upon an IL-1α to IL-6 cascade, whereas LPS and/or turpentine may induce other cytokines, including IL-1β, that either alone or in combination induce glucocorticoids independently of IL-6 (3). The poly I:C–induced responses also appear to occur under conditions of minimal IL-1β expression. Thus, the ability to define the IL-1α to IL-6 pathway for glucocorticoid induction, in response to MCMV and/or poly I:C, is most likely possible because of the absence of parallel or overlapping pathways for induction. A model for pathways of glucocorticoid induction, after viral as compared to bacterial stimulation, is presented in Fig. 5.

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