Cytokines And Glucocorticoid Resistance

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Given the potential role of glucocorticoid resistance in the pathophysiology of major depression, attention has focused on what factors might contribute to glucocorticoid resistance in depression. One interesting possibility involves the immune system. At least two disorders recently have been associated with glucocorticoid resistance in the context of immune activation, including steroid resistant asthma and infection with the human immunodeficiency virus (Miller, Pearce, Ruzek, & Biron, In Press). In both of these cases, cells isolated from relevant patient populations have demonstrated decreased sensitivity to glucocorticoids in vitro, and in both cases, the findings either relate to or can be reproduced by specific cytokines. Work in our own laboratories have also demonstrated that viral infection is associated with changes in GR function (Miller, Spencer, Tanapat, Leung, Dhabhar, McEwen, & Biron, 1997).

Complementary to the notion that immune activation may be involved in the glucocorticoid resistance found in patients with depression is the finding that certain patients with depression exhibit evidence of an activated immune response. Studies have reported elevated serum concentrations of the proinflammatory cytokine, IL-6, as well as increased acute phase proteins including haptoglobin, C-reactive protein and alpha-l-acid glycoprotein in patients with major depression (Maes, 1993; Maes, Meltzer, Bosmans, Bergmans, Vandoolaeghe, Ranjan, & Desnyder, 1995; Sluzewska, Rybakowski, Bosmans, Sobieska, Berghmans, Maes, & Wiktorowicz, 1996; Musselman, Pisell, Lewison, Pearce, Knight, Ninan, Nemeroff, & Miller, 1997). In addition, cellular markers of immune activation have been described (Maes, 1993). The source of the immune activation in major depression is unknown, although studies have shown that stress and CRH are capable of inducing proinflammatory cytokines in the absence of a formal immune challenge (Labeur, Arzt, Wiegers, Holsboer, & Reul, 1995; Schulte, Bamberger, Elsen, Herrmann, Bamberger, & Barth, 1994; Zhou, Kusnecov, Shurin, DePaoli, & Rabin 1993). Elevations in cytokines (especially proinflammatory cytokines like IL-6) have drawn much interest, because cytokines have been shown to have potent stimulatory effects on the HPA axis, in large part through activation of CRH pathways (Besedovsky & del Rey, 1996; Ericsson, Kovacs, & Sawchenko, 1994; Rivier, 1995). Moreover, proinflammatory cytokines have been shown to alter monoamine neurotransmission in multiple brain regions including the hypothalamus (Dunn & Wang, 1995). Finally, administration of cytokines or cytokine inducers have been shown to cause a syndrome of "sickness behavior" in humans and laboratory animals which shares many features in common with major depression including anhedonia, listlessness, altered sleep patterns, reduced appetite and social withdrawal (Kent ct. al., 1992, Yirmiya, 1996). These findings support a role for cytokines in many of the pathophysiological features of depression. Nevertheless, taken together, the evidence of immune activation in depression in conjunction with the association between immune activation and glucocorticoid resistance, it is logical to consider that cytokines might also directly influence GR function leading to glucocorticoid resistance in major depression and thereby participate in the pathophysiology of the disorder.

3.1. Cytokine Effects on GR Expression and Function

There is a large body of data on the impact of cytokines on the GR with over 20 studies documenting significant effects on both GR number and function (for review Miller, et al., In Press). Interestingly, in terms of receptor number, the studies are polarized into those finding increased GR number following cytokine administration and those finding decreased GR number. Of note is that significant technical issues may be confounding the results, since 8 out of 12 studies using whole cell assay binding techniques found GR number to be increased (4 found no change) following treatment with a host of cytokines including 1L-1. IL-2, and IL-4, whereas the majority of studies (6 out of 9) using a cytosolic radioligand binding assay found GR to be decreased (2 found no change) following treatment with the same group of cytokines. Based on findings of increased GR following cytokine treatment, some investigators have posited that relevant cells would be more sensitive to glucocorticoids, however, most studies examining the effects of cytokines (especially, pro-inflammatory cytokines and cytokines that mediate lymphocyte growth and differentiation, e.g., IL-2 and IL-4) on GR function have found inhibition of GR function. In fact, the inhibitory impact of

Table 2. Review of literature: cytokine effects on glucocorticoid receptors

Glucocorticoid receptor number and affinity

— 23 studies identified

Receptor number

— 10 studies found an increase in receptor number following treatment with a host of cytokines and cytokine inducers including TNF, IL-1, IL-6, IL-2. IL-4, IFN-alpha, LPS, and sepsis

— 6 studies found a decrease in receptor number following treatment with a similar group of cytokines and cytokine inducers including TNF, IL-1, IL-6, IFN-beta. and endotoxin

— 9 out of 10 studies that reported an increase in receptor number used a whole cell assay and tended to use longer incubation times

— All 6 studies that reported a decrease in receptor number used a cytosolic radioligand binding assay and tended to use shorter incubation times

Receptor affinity

— 8 studies found a decrease in receptor affinity (increased Kd) following treatment with a host of cytokines and cytokine inducers including TNF. IL-1, IL-6, IL-2, IL-4, IFN-alpha, LPS/endotoxin, and sepsis

Glucocorticoid receptor function

— 8 studies identified

— 5 out of eight demonstrated induction of relative glucocorticoid resistance by cytokines including TNF, IL1 alpha and beta, IL-2, IL-4, and Transforming Growth Factor-beta

— 2 studies reported increased glucocorticoid receptor mediated cellular activity following TNF or IL-1 beta

IL-2 and IL-4 on GR function is hypothesized to play a central role in steroid resistant asthma (Miller et al„ In Press).

To examine potential mechanisms of cytokine effects on GR function, work in our laboratory has focused on the impact of proinflammatory cytokines on GR translocation from cytoplasm to nucleus and hormone-induced, GR-mediated gene transcription. According to the "nucleocytoplasmic traffic" model, the GR in its unactivated form resides primarily in the cytoplasm, and after being bound by steroid undergoes a conformational change ("activation"), dissociates from a multimeric complex including several heat shock proteins (hsp), and translocates from the cytoplasm to the nucleus, where it binds to glucocorticoid response elements (GREs) and interacts with other transcription factors (Guiochon-Mantel, Delabre, Lescop, & Milgrom, 1996). We have evaluated GR translocation in L929 cells (mouse fibroblasts), treated with the proinflammatroy cytokine, IL-1 alpha, for 24 h in the presence or absence of the synthetic steroid, DEX (Pariante, Pearce, Pisell, & Miller, 1996). Our initial characterizations of cytokine-GR interactions were with IL-1 alpha, because much of the focus on neuroendocrine-immune interactions has been based on the neuroendocrine effects of IL-1, and recent work in our experimental murine viral infections has shown that IL-lalpha in particular induces IL-6 to stimulate a surge in endogenous glucocorticoids during infection with murine cytomegalovirus (MCMV) (Ruzek, Miller, Opal, Pearce, & Biron, 1997). GR translocation was investigated using GR immunostaining and cytosolic radioligand receptor binding. In addition, GR-mediated gene transcription was measured by means of L929 cells stably transfected with the MMTV-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene which is under hormonal control by virtue of several GREs residing within the MMTV-LTR region (upstream of the CAT reporter gene). IL-lalpha was found to both increase receptor protein expression in the cytoplasm, and block GR translocation from the cytoplasm to the nucleus in cells that were pretreated with IL-1 alpha. In addition, in cells that were either pretreated with IL-1 alpha and then incubated with DEX or coincubated with IL-1 alpha plus DEX for 24 hours, there was a significant reduction in DEX-induced GR-mediated gene transcription. These results suggest that proinflammatory cytokines like IL-1 may have direct effects on GR function which lead to glucocorticoid resistance. These results also might explain the mechanism underlying glucocorticoid resistance (dexamethasone nonsuppression) found in animals chronically treated with LPS (Weidenfeld & Yirmiya, 1996) and in patients with HIV infection (Norbiato, Bevilacqua, & Vago, 1997).

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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