Comprehensive Physiology Wiley Online Library

Interactions Between the Hypothalamic‐Pituitary‐Adrenal Axis and Immune System During Viral Infection: Pathways for Environmental Effects on Disease Expression

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Immune Responses to Viral Infection
1.1 Early Innate Immunity
1.2 Late Adaptive Immunity
2 Pathology During Viral Infection
2.1 Cell‐Mediated Pathology
2.2 Cytokine‐Mediated Pathology
3 Cytokine Pathways for Glucocorticoid Induction During Viral Infection [“Starting the Loop”]
3.1 Glucocorticoid Induction during Viral Infection
3.2 Cytokines and Glucocorticoid Induction during Viral Infection
4 Central Nervous System/Neuroendocrine Pathways for Glucocorticoid Induction During Viral Infection (“Making the Connection”)
4.1 Pathways by which Peripheral Cytokine Signals Reach the Brain
4.2 Cytokine Network in the Central Nervous System
4.3 Cytokines and Behavior
5 Viral Infection, Glucocorticoid Availability, and Glucocorticoid Receptor Expression and Function (“Delivering and Receiving The Signal”)
5.1 Corticosteroid‐Binding Globulin and 11β‐Hydroxysteroid Dehydrogenase
5.2 Glucocorticoid Receptor Changes during Viral Infection
5.3 Cytokines as Potential Mediators of Glucocorticoid Receptor Changes during Viral Infection
6 Endogenous Glucocorticoids and Host Responses to Viral Infection (“Shaping The Response, Protection, and Closing the Loop”)
6.1 Impact of Stress on Immune Responses to Viral Infection
6.2 Glucocorticoids as the Mediator of Stress Effects on Viral Immunity
7 Summary
Figure 1. Figure 1.

Steps in bidirectional communication between immune system and neuroendocrine system following viral infection. Immune activation leads to release of cytokines (starting the loop), which in turn activate central neuroendocrine circuits (making the connection). Released glucocorticoids then interact with their receptors on target immune tissues (delivering the signal and receiving the signal) and modulate immune responses to the virus (shaping the response) including cytokine release (closing the loop). CRH, Corticotropin‐releasing hormone; ACTH, corticotropin; IL, interleukin; TNF, tumor necrosis factor.

Figure 2. Figure 2.

Potential glucocorticoid effects on known cellular and cytokine responses to viral infection. IFN, interferon; IL, interleukin; NK, natural killer; TNF, tumor necrosis factor; TGF, transforming growth factor; CTL, cytotoxic T lymphocyte; Ab, antibody.

Figure 3. Figure 3.

Kinetics and relative magnitudes of cellular and cytokine responses to lymphocytic choriomeningitis virus (LCMV) or murine cytomegalovirus (MCMV) infection. Early natural killer (NK) cell activity peaks between days 1 and 3 following infection and corresponds with induction of systemic interferon (IFN)‐αβ as well as other proinflammatory cytokine responses, depending on the infection. Later T‐cell responses, peaking 7 to 9 days following infection, are associated with local (splenic) production of T cell‐derived cytokines and are more prominent during LCMV infection than MCMV infection. Representation of cytokine expression is based on results discussed in the text and ongoing studies in our laboratory: IFN‐α/β (; unpublished data), interleukin (IL)‐12 , IFN‐γ, IL‐2 , IL‐4 , IL‐6 (; unpublished data), IL‐10 (unpublished data), tumor necrosis factor (TNF)‐α (; unpublished data), and transforming growth factor (TGF)‐β .

Figure 4. Figure 4.

Kinetics and magnitudes of endogenous glucocorticoid responses vary depending on viral challenge. Serum corticosterone responses to polyinosinic‐polycytidylic acid (polyI:C) administration and during viral infections are shown. Mice were injected with 100 μg poly I:C (A) or infected with 2 × 104 plague‐forming units (PFU) of lymphocytic choriomeningitis virus (LCMV) clone E350 (B), 5 × 104 PFU murine cytomegalovirus (MCMV) (C) or 1 × 106 PFU LCMV clone 13 (D). Serum samples were collected under low‐stress conditions during the morning and examined for levels of serum corticosterone. Harvests were at indicated times following treatment or infection. Data are means ± standard error of at least three mice per group. [A is from Miller et al. ] with permission.

Figure 5. Figure 5.

InterIeukin‐6 (IL‐6) plays a pivotal role in the induction of endogenous glucocorticoids in response to viral challenges. Serum corticosterone levels following murine cytomegalovirus (MCMV), lipopolysaccharide (LPS), polyinosinic‐polycytidylic acid (polyI:C), or restraint stress administration in IL‐6‐deficient and wild‐type mice. Corticosterone levels were measured in serum collected from mice under low‐stress conditions (less than 4 min of handling) at 36 h following infection with 5 × 104 plague‐forming units MCMV (A); 2 h following injection with phosphate‐buffered saline (PBS), 50 μg LPS, or 100 μg polyI:C (B); or after 30 min of restraint (C). Data are means ± standard error of four mice per group. Results are significant at *P<0.05.

B and C are from Ruzek et al. with permission © The Rockefeller University Press
Figure 6. Figure 6.

The upstream hypothalamic‐pituitary‐adrenal axis hormone corticotropin (ACTH) is induced during infection with murine cytomegalovirus (MCMV). Serum corticosterone and corticotropin levels following MCMV infection were measured in serum samples collected from C57BL/6 mice under low‐stress conditions (mice were bled within 4 min of handling for corticosterone measurement and within 2 min of handling for corticotropin measurement). Serum corticosterone was measured at 2 to 4 h intervals between 24 and 48 h (A), and serum corticotropin was measured at 4 to 6 h intervals between 18 and 36 h (B) following MCMV (5 × 104 plague‐forming units/mouse) or vehicle injection. A: Data are means ± standard deviation of two mice per time point. B: Data are means ± standard error of three mice per time point. Results are significant at *P< 0.05 and **P< 0.01.

From Ruzek et al. with permission. © The Rockefeller University Press
Figure 7. Figure 7.

Model for virus‐induced cytokine and glucocorticoid interactions during viral infection. The induction of cytokines by viral infection activates the hypothalamic‐pituitary‐adrenal (HPA) axis and the release of glucocorticoids. Glucocorticoids, in turn, suppress cytokine production and limit both the pathological and the antiviral effects of these cytokines. Genetic and environmental influences contribute to glucocorticoid responses during infection by shaping HPA axis sensitivity and the degree of glucocorticoid induction. Thus, the HPA axis regulates the precarious balance between deleterious and beneficial immune responses to viral infection. This model is representative of events demonstrated during murine cytomegalovirus infection but may apply to additional cytopathic viruses that induce early systemic cytokine responses. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.



Figure 1.

Steps in bidirectional communication between immune system and neuroendocrine system following viral infection. Immune activation leads to release of cytokines (starting the loop), which in turn activate central neuroendocrine circuits (making the connection). Released glucocorticoids then interact with their receptors on target immune tissues (delivering the signal and receiving the signal) and modulate immune responses to the virus (shaping the response) including cytokine release (closing the loop). CRH, Corticotropin‐releasing hormone; ACTH, corticotropin; IL, interleukin; TNF, tumor necrosis factor.



Figure 2.

Potential glucocorticoid effects on known cellular and cytokine responses to viral infection. IFN, interferon; IL, interleukin; NK, natural killer; TNF, tumor necrosis factor; TGF, transforming growth factor; CTL, cytotoxic T lymphocyte; Ab, antibody.



Figure 3.

Kinetics and relative magnitudes of cellular and cytokine responses to lymphocytic choriomeningitis virus (LCMV) or murine cytomegalovirus (MCMV) infection. Early natural killer (NK) cell activity peaks between days 1 and 3 following infection and corresponds with induction of systemic interferon (IFN)‐αβ as well as other proinflammatory cytokine responses, depending on the infection. Later T‐cell responses, peaking 7 to 9 days following infection, are associated with local (splenic) production of T cell‐derived cytokines and are more prominent during LCMV infection than MCMV infection. Representation of cytokine expression is based on results discussed in the text and ongoing studies in our laboratory: IFN‐α/β (; unpublished data), interleukin (IL)‐12 , IFN‐γ, IL‐2 , IL‐4 , IL‐6 (; unpublished data), IL‐10 (unpublished data), tumor necrosis factor (TNF)‐α (; unpublished data), and transforming growth factor (TGF)‐β .



Figure 4.

Kinetics and magnitudes of endogenous glucocorticoid responses vary depending on viral challenge. Serum corticosterone responses to polyinosinic‐polycytidylic acid (polyI:C) administration and during viral infections are shown. Mice were injected with 100 μg poly I:C (A) or infected with 2 × 104 plague‐forming units (PFU) of lymphocytic choriomeningitis virus (LCMV) clone E350 (B), 5 × 104 PFU murine cytomegalovirus (MCMV) (C) or 1 × 106 PFU LCMV clone 13 (D). Serum samples were collected under low‐stress conditions during the morning and examined for levels of serum corticosterone. Harvests were at indicated times following treatment or infection. Data are means ± standard error of at least three mice per group. [A is from Miller et al. ] with permission.



Figure 5.

InterIeukin‐6 (IL‐6) plays a pivotal role in the induction of endogenous glucocorticoids in response to viral challenges. Serum corticosterone levels following murine cytomegalovirus (MCMV), lipopolysaccharide (LPS), polyinosinic‐polycytidylic acid (polyI:C), or restraint stress administration in IL‐6‐deficient and wild‐type mice. Corticosterone levels were measured in serum collected from mice under low‐stress conditions (less than 4 min of handling) at 36 h following infection with 5 × 104 plague‐forming units MCMV (A); 2 h following injection with phosphate‐buffered saline (PBS), 50 μg LPS, or 100 μg polyI:C (B); or after 30 min of restraint (C). Data are means ± standard error of four mice per group. Results are significant at *P<0.05.

B and C are from Ruzek et al. with permission © The Rockefeller University Press


Figure 6.

The upstream hypothalamic‐pituitary‐adrenal axis hormone corticotropin (ACTH) is induced during infection with murine cytomegalovirus (MCMV). Serum corticosterone and corticotropin levels following MCMV infection were measured in serum samples collected from C57BL/6 mice under low‐stress conditions (mice were bled within 4 min of handling for corticosterone measurement and within 2 min of handling for corticotropin measurement). Serum corticosterone was measured at 2 to 4 h intervals between 24 and 48 h (A), and serum corticotropin was measured at 4 to 6 h intervals between 18 and 36 h (B) following MCMV (5 × 104 plague‐forming units/mouse) or vehicle injection. A: Data are means ± standard deviation of two mice per time point. B: Data are means ± standard error of three mice per time point. Results are significant at *P< 0.05 and **P< 0.01.

From Ruzek et al. with permission. © The Rockefeller University Press


Figure 7.

Model for virus‐induced cytokine and glucocorticoid interactions during viral infection. The induction of cytokines by viral infection activates the hypothalamic‐pituitary‐adrenal (HPA) axis and the release of glucocorticoids. Glucocorticoids, in turn, suppress cytokine production and limit both the pathological and the antiviral effects of these cytokines. Genetic and environmental influences contribute to glucocorticoid responses during infection by shaping HPA axis sensitivity and the degree of glucocorticoid induction. Thus, the HPA axis regulates the precarious balance between deleterious and beneficial immune responses to viral infection. This model is representative of events demonstrated during murine cytomegalovirus infection but may apply to additional cytopathic viruses that induce early systemic cytokine responses. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

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Andrew H. Miller, Bradley D. Pearce, Melanie C. Ruzek, Christine A. Biron. Interactions Between the Hypothalamic‐Pituitary‐Adrenal Axis and Immune System During Viral Infection: Pathways for Environmental Effects on Disease Expression. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 425-450. First published in print 2001. doi: 10.1002/cphy.cp070419