Effect of Steroids on Lipopolysaccharide/Interleukin 2-Induced Interleukin 18 Production in Peripheral Blood Mononuclear Cells

Abstract

Interleukin (IL) 18, a powerful inducer of the immunoregulatory cytokine interferon-gamma (IFN-gamma), presents upstream of the cytokine activation cascade in the inflammatory response. The anti-inflammatory properties of steroids permit their use in various conditions, although effects are transient and pathological states are not fully relieved by short-term steroidal use. We examined the effect of lipopolysaccharide (LPS)/IL-2 on the cytokine cascade in human peripheral blood mononuclear cells (PBMCs). We also examined the effect of steroids on LPS/IL-2-induced cytokine production in human PBMCs taken from healthy volunteers. Cell-free supernatant fractions were assayed for IL-18, IL-12, IL-2, IFN-gamma and IL-10 protein, using enzyme-linked immunosorbent assays, and synergy between LPS and IL-2 in enhanced production of IL-18 was observed. Steroids suppressed the production of IL-18 and other secondary cytokines in LPS/IL-2-stimulated PBMCs, in a concentration- and time-dependent manner, although inhibition was incomplete even at high concentrations. Effects of steroid treatment on expression of membrane-bound LPS receptor antigen (mCD14) and intercellular adhesion molecule-1 (ICAM-1) in PBMCs were studied by flow cytometric analysis. Steroid treatment up-regulated mCD14 expression in a concentration-dependent manner, with no effect on ICAM-1 expression. These results suggest that the incomplete counteraction of steroids in the LPS/IL-2-initiating cytokine cascade is due, at least partly, to the up-regulation of mCD14 by steroid preparations, which increases susceptibility to bacterial endotoxins.

Glucocorticoids and the Th1/Th2 Balance

“…GCs also suppress the production of IL-18 (which synergizes with IL-12 to promote Th1 responses) in LPS/IL-2-stimulated peripheral blood mononuclear cells (PBMCs), although the inhibition seems to be incomplete even at high concentrations. 16 This is consistent, however, with an observation that in GC-responsive patients with Graves' ophthalmopathy the GCs treatment results in decreased IL-18 serum concentrations as compared to the pretreatment values. 17 GCs also inhibit the production of IFN-γ, another cytokine that synergizes with IL-12 to promote Th1 responses-in PBMCs of healthy adult volunteers stimulated with Newcastle disease virus (NDV), GCs reduce the IFN-α release by 50 to 60%.…”

“…25,26 Furthermore, the synthesis of transforming growth factor (TGF)-β, another cytokine with potent anti-inflammatory activities, is enhanced by GCs in human T cells but suppressed in glial cells, 27 and low concentra-tions of dexamethasone can indeed activate alveolar macrophages, leading to increased LPS-induced IL-1β production. 28 In contrast to the abovementioned inhibitory effect of GCs on the production of IL-18 by LPS/IL-2-stimulated PBMCs, 16 in cultured unstimulated PBMC and promonocytic cell lines, prednisolone upregulates IL-18 transcription in parallel with increasing the IL-18 protein release into cell culture supernatants. 29 It is highly likely that GCs downregulate IL-18 production in activated macrophages but upregulate IL-18 production in resting, non-activated cells.…”

Interleukin-18 production and pulmonary function in COPD

“…These results suggest that IL-18 production may not be influenced by ICS treatment. However, a previous study [34] reported that steroids suppressed the production of IL-18 in lipopolysaccharide-/IL-2-stimulated peripheral blood mononuclear cells in vitro. Further analysis is needed to verify whether steroids can influence IL-18 production in COPD patients.…”

Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ETBReceptors in Rats

“…It is important to mention that the patients under IL-12 treatments that reported pain, described in the above clinical study (Gollob et al, 2000;Lenzi et al, 2002;Weiss et al, 2003), were not receiving glucocorticosteroid therapy. Glucocorticosteroids are known inhibitors of the synthesis of eicosanoids (prostaglandins and leukotrienes), proinflammatory cytokines such as TNF-␣, IL-2, IL-1␤, IL-6, and IL-18 (for review, see Goulding, 1998;Kodama et al, 2002) and endothelin (Dschietzig et al, 2001). Thus, taking into account the above results indicating that prostanoids, leukotrienes, TNF-␣, and IL-18 were not involved in the IL-12-induced hyperalgesia, the possible involvement of endothelin and its receptor subtypes was addressed.…”