High-dose dexamethasone regulates interleukin-18 and interleukin-18 binding protein in idiopathic thrombocytopenic purpura

Abstract

| 1603 | Brief Report IntroductionInterleukin-18 (IL-18), a member of IL-1 cytokine family, is a potent interferon-γ (IFN-γ) inducing factor and is synthesized by Kupffer cells in the liver, pancreas, kidney, skeletal muscle, lung, osteoblasts, and keratinocytes.1-3 IL-18 binding protein (IL-18BP) is a constitutively secreted protein able to bind IL-18 with high affinity, providing a potential mechanism whereby IL-18 activity is regulated. 4 Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, characterized by early platelet destruction induced by autoantibodies directed against specific glycoproteins of platelet surface. 5,6 It has become evident that an increased Th1/Th2 ratio in the peripheral blood has been proposed to correlate with disease activity in ITP .7-9 The expression of IFN-γ, a typical Th1 cytokine, is significantly higher in active ITP patients. Our previous study confirmed that the plasma and mRNA levels of both IFN-γ and IL-18 in active ITP patients were increased significantly compared with the normal controls. And the plasma concentrations of IL-18 correlated with IFN-α. We also observed IL-18BP was not significantly elevated in ITP patients, which resulted in an elevated ratio of IL-18/IL-18BP in patients with active disease. The balance of IL-18/IL-18BP plays a role in progression of ITP. 10Glucocorticoids (GC) have been widely recognized as the most appropriate first-line treatment for ITP, 11 even if the best therapeutic approach is still a matter of debate. Recently, highdose dexamethasone (HD-DXM) in 4-day cycles has proven its clinical efficacy in the treatment of ITP.12,13 However, the effects of HD-DXM on the balance of IL-18/IL-18BP remains unclear. In the present study, plasma levels as well as mRNA expression of IL-18, IL-18BP in peripheral blood mononuclear cells (PBMCs) and in vitro PBMC cultivation were measured to investigate possible effects of HD-DXM on IL-18 activity in ITP patients. Design and Methods Clinical studySeventeen patients with newly diagnosed ITP (13 females and 4 males, age range 16-58 years, median 38 years) were Funding: this work was supported by grants from National Natural Science Foundation of China (30600259, 30600680, 30770922, 30800491, and 30801258), 973 Program (N. 2006 CB 503803) China 2007, and Taishan scholar project funding. Manuscript received on February 23, 2009. Revised version arrived on April 9, 2009. Manuscript accepted on May 11, 2009 To evaluate the effects of high-dose dexamethasone (HD-DXM) on the balance of interleukin-18 (IL-18) and its endogenous antagonist IL-18 binding protein (IL-18BP) in ITP patients, IL-18, IL-18BP as well as IFN-γ, IL-4 plasma levels and platelet counts were determined in 17 ITP patients receiving DXM 40 mg/day for four consecutive days and in 24 healthy subjects. Using RT-PCR, the mRNA expression of IL-18, IL-18BP, IFN-γ, IL-4, T-box (T-bet) and GATA-binding protein 3(GATA-3) were studied in all subjects. The in vitro effects of DXM on IL-18BP and IL-18 of peripheral blood mononuclear cells ...

Absence of Association ofInterleukin-18Gene Polymorphisms with Primary Immune Thrombocytopenia in a Chinese Han Population

“…As a proinflammatory cytokine, it was upregulated in some autoimmune diseases and often in correlation with disease activity (Migliorini et al, 2010). It is reported that the serum IL-18 concentrations in ITP patients were higher compared with normal controls, which confirmed that IL-18 were involved in ITP pathogenesis (Shan et al, 2009b). For the -607 C/A and -137 G/C polymorphisms to cause transcription factor binding and regulate gene expression (Giedraitis et al, 2001), we speculated that there was a correlation between IL-18 promoter polymorphisms and the clinical implications of ITP.…”

“…GCs, as a first-line therapy strategy, were widely used in ITP treatment. The research about the mechanism of GC treatment in ITP patients demonstrated that high-dose dexamethasone administration could downregulate IL-18 expression in ITP patients (Shan et al, 2009b), suggesting that GCs work in ITP patients partly by downregulation of IL-18. Thus, in this study, we also analyzed the association between IL-18 polymorphisms and the clinical responses to GC treatment, but no significant association was found.…”

“…The elevated levels of IL-18 might enhance Th1 immune responses, including excessive IFN-g and TNF-a production, finally leading to exacerbation of ITP (Shan et al, 2009a). In addition, high-dose dexamethasone administration could downregulate IL-18 expression in ITP patients (Shan et al, 2009b), validating the important role of IL-18 in ITP pathogenesis.…”

Recent progress in understanding the pathogenesis of immune thrombocytopenia

“…IL-18 is generally produced by macrophages and induces severe proinflammatory processes via its ability to stimulate Th1 cells and natural killer (NK) cells to secrete large quantities of interferon (IFN)-g [41]. Shan et al [42] showed significantly increased levels of IL-18 and IFN in patients with active ITP, whereas in patients in remission the plasma IL-18 levels were similar to healthy controls. Subsequently, a corresponding increase in the IL-18 antagonist, IL-18 binding protein, was noted in patients in remission [43 ].…”

Imbalance of Interleukin-18 and Interleukin-18 Binding Protein in Children with Henoch-Schönlein Purpura

“…31,32 IL-18BP is induced by IFN-γ, thus establishing a negative feedback loop that can be observed in vitro and in vivo; it has been shown that IL-18BP inhibits the production of IL-18-induced IFN-γ and IL-8 production, the activation of nuclear factor κ-light chain enhancer of activated B cells in vitro and the production of lipopolysaccharide-induced IFN-γ production in vivo. 33 -35 Elevated plasma levels of IL-18BP have been reported in idiopathic thrombocytopenic purpura, 13,14 Crohn's disease, 36 inflammatory bowel disease in children and other diseases. 37 -39 The present study is the first to report on the balance between plasma IL-18 and IL-18BP levels in HSP patients.…”