Interleukin-6 and the development of social disruption-induced glucocorticoid resistance

doi:10.1016/S0165-5728(02)00004-8

Journal of Neuroimmunology

Volume 124, Issues 1–2, March 2002, Pages 9-15

https://doi.org/10.1016/S0165-5728(02)00004-8 Get rights and content

Abstract

Following social disruption (SDR) stress in male mice, corticosterone resistance of splenocytes was accompanied by enhanced LPS-stimulated interleukin (IL)-6 secretion. The present study examined the role of IL-6 in the development of corticosterone resistance. Addition of IL-6 to control splenocyte cultures did not induce corticosterone resistance. SDR also elevated IL-6 in plasma and liver, but not in spleen. IL-6 deficient mice that were exposed to SDR developed glucocorticoid resistance despite the absence of systemic IL-6. These findings suggest that although SDR enhanced IL-6 responses, IL-6 was not essential for the development of stress-induced splenocyte corticosterone resistance.

Introduction

Interleukin (IL)-6 is a cytokine which is primarily produced by monocytes/macrophages in response to inflammatory stimuli. Gram-negative bacterial infections or polyclonal activation by a mitogen, such as lipopolysaccharide (LPS), are known to stimulate an IL-6 response. IL-6 plays diverse roles in the immune system, including promotion of T cell proliferation and differentiation of antibody-secreting B cells. IL-6 is released in tissues or systemically in response to a variety of homeostatic challenges. Skin damage, such as surgical incision, was found to increase expression of IL-6 in a number of cell types (Ueo et al., 1994). Serum or plasma IL-6 was elevated following burns (Guo et al., 1990), surgical procedures (Cruickshank et al., 1990), and trauma (Gebhard et al., 2000), and tended to be higher with more severe injuries. In rodents, restraint stress has been shown to increase plasma IL-6 Nukina et al., 1998, Zhou et al., 1993.

In addition to these acute conditions, IL-6 has been found to be associated with certain chronic disorders. For example, patients with major depression have been reported to have elevated plasma IL-6 (Maes et al., 1997), as well as increased production of IL-6 by mitogen-stimulated peripheral blood mononuclear cells (Maes et al., 1993). Depression has also been linked to altered feedback control of glucocorticoid hormones in central pathways and in peripheral immune cells Lowy et al., 1984, Miller et al., 1999. Furthermore, production of IL-6 by peripheral leukocytes was positively correlated with central glucocorticoid resistance (Maes et al., 1993).

Our laboratory has been studying the induction of peripheral glucocorticoid resistance following social disruption (SDR) stress in male mice. Six 2-h stress cycles over the course of a week induced splenomegaly. In addition, LPS-stimulated splenocytes from SDR mice were insensitive to the anti-proliferative effects of corticosterone Avitsur et al., 2001, Stark et al., 2001, and produced elevated levels of IL-6 (Stark et al., 2001). Enhanced IL-6 production always accompanied glucocorticoid resistance, and both lasted for between 10 and 30 days after the final cycle of SDR (Avitsur et al., 2002, in press). Glucocorticoids provide negative regulation over the immune system, and corticosterone resistance has been found to result in excessive inflammatory responses following in vivo challenge with LPS (Quan et al., 2001).

It was unclear whether the enhanced IL-6 response of cells from SDR mice contributed to the development of the glucocorticoid resistant state. The present studies found that SDR increased plasma IL-6, and investigated whether either spleen-derived or systemic IL-6 was involved in the development of corticosterone resistance. In vitro addition of IL-6 to LPS-stimulated splenocytes, to mimic the IL-6 production by LPS-stimulated SDR splenocytes, was not sufficient to induce resistance. Furthermore, SDR-induced corticosterone resistance developed to a similar degree in both wild-type and IL-6 deficient mice. These results showed that although increased IL-6 accompanied SDR-induced splenic glucocorticoid resistance, it was not required for the development of the resistance.

Section snippets

Animals

For most experiments, male C57BL/6 mice were ordered from Charles River (Wilmington, MA). For the IL-6 knock-out study, male B6.129S6-Il6^tm1Kopf mice and the background control C57BL/6J mice were ordered from Jackson Laboratory (Bar Harbor, ME). Experimental animals were received at 6–8 weeks old, were housed 5 per cage, and were allowed to acclimate for at least one week before any procedures began. Mice were maintained on a 12 h light/dark cycle (lights on at 6 AM) in an American Association

Effect of social disruption on splenocyte sensitivity to corticosterone

Male mice remained undisturbed in their home cages or were exposed to six 2 h evening cycles of social disruption (SDR) stress. Animals were sacrificed the morning after the final stress session and splenocytes were cultured with LPS and increasing concentrations of corticosterone. In agreement with previously reported results (Stark et al., 2001), splenocytes from mice that experienced SDR stress secreted increased levels of IL-6 during 18 h of stimulation. Compared to cells from control mice,

Discussion

These studies showed that social stress enhanced IL-6 responses in plasma, as well as in LPS-stimulated splenocytes as previously reported Avitsur et al., 2001, Stark et al., 2001. Plasma IL-6 was elevated immediately after the first but not the final cycle of SDR, suggesting that the mice may adapt to repeated exposure to the stressor. Other studies have found that circulating IL-6 is increased by physical or psychological stress Nukina et al., 1998, Zhou et al., 1993 and by tissue injury

Acknowledgements

We are grateful to Dr. F. Michael Beck for assistance with statistical analyses. We thank Kari Kramer and Patty Guerra for help with the animal work and Kari Kramer for excellent technical assistance with the IL-6 ELISA. These studies were supported by grants from the NIMH (F31 MH11792 to J.L.S. and RO1 MH46801-08 to J.F.S.), and the John D. and Catherine T. MacArthur Foundation Mind-Body Network.

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Interleukin-6 and the development of social disruption-induced glucocorticoid resistance

Abstract

Introduction

Section snippets

Animals

Effect of social disruption on splenocyte sensitivity to corticosterone

Discussion

Acknowledgements

Social stress induces glucocorticoid resistance in subordinate animals

Horm. Behav.

Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids

Endocr. Rev.

The acute phase response

Immunol. Today

Glucocorticoid-resistant asthma: T-lymphocyte defects

Am. J. Respir. Crit. Care Med.

Response of serum interleukin-6 in patients undergoing elective surgery of varying severity

Clin. Sci.

Is interleukin 6 an early marker of injury severity following major trauma in humans?

Arch. Surg.

Increased levels of circulating interleukin 6 in burn patients

Clin. Immunol. Immunopathol.

Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone

Am. J. Psychiatry

Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic–pituitary–adrenal axis in severe depression

Psychiatry Res.

Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression

Cytokine

Effects of cytokines on glucocorticoid receptor expression and function: glucocorticoid resistance and relevance to depression