Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

Abstract

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.

Cytokine (TNFα, LTα and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies

“…This is in agreement with previous studies showing that steroids broadly attenuate cytokine production not only of pro-inflammatory TNF␣, but also of the anti-inflammatory IL-10. 24 Interestingly, we observed that 5-ASA usage was associated with higher IL-10 secretion and like smoking could therefore act through a feedback control.…”

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

“…The pathogenic mechanisms in patients with HLA DR4 may be more dependent on cytokines modified by corticosteroid therapy than patients with HLA DR3. 40,41 Alternatively, the responsiveness of the elderly to corticosteroid therapy may reflect in part age-related changes in immune reactivity. Aging alters immune responsiveness by decreasing the expression of HLA class II molecules 42 and reducing stimulation and proliferation of antigen-stimulated T cells.…”

Chlamydial infection of polarized HeLa cells induces PMN chemotaxis but the cytokine profile varies between disseminating and non-disseminating strains

“…At the relatively low concentration of cycloheximide used (1 mg ml 21 ) in our experiments, translation of the superinduced transcripts may not be completely abolished, thus explaining such increases in the protein amounts. As cycloheximide exposure had little effect in abolishing cytokine release by C. trachomatis-infected HeLa cells, infected cultures were subsequently examined, especially for IL-11 and IL-6 production, following exposure to dexamethasone, a glucocorticoid known to modulate cytokine production (Brattsand and Linden, 1996;Wang et al, 1999). At a concentration of 10 26 M, dexamethasone induced a dramatic decrease in IL-8 (71% reduction), IL-11 (97% reduction) and IL-6 (95% reduction) release by L2-infected cells compared with unexposed infected cells (Table 3).…”