The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-gamma growth inhibition of human breast carcinoma cell lines.

Interferon (IFN) regulatory factor-1 (IRF-1) and IRF-2 play opposing roles in the regulation of many IFN-gamma-inducible genes. To investigate the signal transduction pathway in response to IFN-gamma in light of differences in growth effects, we selected four human breast carcinoma cell lines based on a spectrum of growth inhibition by IFN-gamma. MDA468 growth was markedly inhibited by IFN-gamma, and it showed substantial induction of IRF-1 mRNA but little IRF-2 induction. SKBR3 showed little growth inhibition and little induction of IRF-1 mRNA but significant induction of IRF-2 mRNA. HS578T and MDA436 growth inhibition and IRF-1/IRF-2 induction were intermediate. All four cell lines showed intact receptor at the cell surface and Stat1 translocation to the nucleus by immunostaining. By EMSA, there were marked differences in the induced ratio of IRF-1 and IRF-2 binding activity between the cell lines that correlated with growth inhibition. Finally, antisense oligonucleotides specific for IRF-1 attenuated IFN-gamma growth inhibition in MDA436 and MDA468, confirming the direct role of IRF-1 in IFN-gamma growth inhibition. Induction of IRF-1 causes growth inhibition in human breast cancer cell lines, and induction of IRF-2 can oppose this. The relative induction of IRF-1 to IRF-2 is a critical control point in IFN-gamma response.     

Experimental autoimmune thyroiditis in nonobese diabetic mice lacking interferon regulatory factor-1

Interferon regulatory factor-1 (IRF-1) is pivotal in the regulation of interferon (IFN)-mediated immune reactions, and studies suggest that IRF-1 is involved in the development of autoimmune diseases. IRF-1+/+, +/-, and -/- nonobese diabetic (NOD) mice were immunized with mouse thyroglobulin (mTg) to determine whether IRF-1 is required in experimental autoimmune thyroiditis (EAT), a murine model for Hashimoto's thyroiditis (HT). IRF-1-deficient mice developed EAT and anti-mTg antibodies comparable to IRF-1+/+ and +/- mice. Whereas both CD4+ and CD8+ T cells were found in thyroids of IRF-1+/+ mice, the latter was not in IRF-1-/- mice. Major histocompatibility complex class II antigen was comparably expressed in thyroids of IRF-1+/+ and -/- mice. Lack of IRF-1 resulted in decreased CD8+ T cell number in the spleen and reduced IFNgamma production by splenocytes. Our results suggest that IRF-1 is not pivotal in EAT in NOD mice.     

IL-10对脑缺氧复氧后干扰素调节因子-1表达的抑制作用

目的:探讨白介素-10(IL-10)对缺氧复氧后干扰素调节因子-1(IRF-1)表达的作用。方法:采用缺氧8h复氧2h法建立脑微血管内皮细胞和中性粒细胞共培养缺氧复氧模型。实验分组:正常对照组,缺氧复氧组、IL-10干预组,其中IL-10干预组根据浓度不同分为1μg/L组、10μg/L组和30μg/L组。RT-PCR和Western blot检测IRF-1表达的变化。结果:缺氧复氧组IRF-1表达较正常组显著升高(P0.05)。IL-10干预组IRF-1表达较缺氧复氧组显著下降,并与IL-10剂量有关,呈剂量依赖性,在30μg/L表达最低(P0.05)。结论:IL-10可显著抑制脑缺氧复氧后IRF-1的表达。     

Multitasking of interferon regulatory factor-4 in early B cells

Immunoglobulin heavy- and light-chain genes are rearranged in a temporally ordered manner. In this issue, Johnson et al. (2008) show that interferon regulatory factor-4 regulates light-chain gene rearrangement by activating enhancers and attenuating interleukin-7 signaling.     

IFN-alpha and IL-18 exert opposite regulatory effects on the IL-12 receptor expression and IL-12-induced IFN-gamma production in mouse macrophages: novel pathways in the regulation of the inflammatory response of macrophages

We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN-gamma production by cytokines (IFN-alpha and IL-18) and regulation of IL-12 receptor expression. Beta1 and beta2 IL-12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL-12 for IFN-gamma production. Expression of the IL-12R beta1 chain mRNA was increased further following IL-12 treatment as a consequence of IFN-gamma expression. IL-12 response was regulated differentially by IFN-alpha and IL-18. Neutralization of endogenous type I IFN increased IFN-gamma secretion, whereas exogenous IFN-alpha reduced it. In contrast, IL-18 enhanced IFN-gamma mRNA accumulation and IFN-gamma secretion in IL-12-stimulated, but not -untreated, cultures. The opposite effects exerted by IFN-alpha and IL-18 mirror their mutual capacity of regulating-in a negative or positive manner, respectively-the expression of the IL-12R beta1 chain. We suggest that differential regulation of IL-12 response by IFN-alpha and IL-18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.     

Cytokine regulation of human monocyte interleukin-1 (IL-1) production in vitro. Enhancement of IL-1 production by interferon (IFN) gamma, tumour necrosis factor-alpha, IL-2 and IL-1, and inhibition by IFN-alpha.

IL-1 production (secreted and cell-associated) was measured in monocyte cultures stimulated by a variety of agents in vitro. Monocytes either adherent to conventional plastic culture plates in serum-free conditions, or in suspension in culture medium containing serum were stimulated to produce IL-1 during culture. In non-adherent, serum-free conditions, monocytes produced very low or undetectable amounts of IL-1 during 20 h of culture. Lipopolysaccharide (LPS) induced equivalent amounts of secreted and cell-associated IL-1, although at very low concentrations more cell-associated IL-1 was produced. IL-1 production in response to LPS could be augmented by crude lymphokine, IFN-gamma, or tumour necrosis factor (TNF) alpha. TNF-alpha preferentially augmented the production of cell-associated IL-1 in LPS-stimulated cultures. TNF-alpha induced a significant amount of IL-1 (mainly cell-associated) directly but could also induce IL-1 secretion when combined with IL-2 or IFN-gamma, or when in the presence of serum. IL-2 acted synergistically with low concentrations of IFN-gamma or IL-1 to induce significant levels of IL-1 production. IFN-alpha did not induce any IL-1 production, but was a potent inhibitor of IL-1 production induced by a variety of stimuli. These results suggest that IL-1 production may be enhanced or reduced by different cytokines at concentrations likely to be found in chronic inflammatory lesions.     

Role of interferon regulatory factor-mediated signaling in psoriasis

Psoriasis is a chronic inflammatory disease that involves both the innate and adaptive immune systems. Type I interferons (IFNs), the production of which is partially regulated by toll-like receptors (TLRs), play an important role in the pathogenesis of psoriasis, especially psoriasis caused by skin trauma, known as the Koebner phenomenon. IFN regulatory factors (IRFs) function in both innate and adaptive immune responses, and their effect is associated with the regulation of type I IFNs. In this review, we focus on recent advances in understanding the expression of TLRs, IRFs, and type I IFNs in psoriasis. We also highlight the interplay among TLRs, IRFs, and type I IFNs.     

Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia

The cannabinoid type-2 G protein-coupled (CB₂) receptor is an emerging therapeutic target for pain management and immune system modulation. In a mouse model of Alzheimer??s disease (AD) the orally administered natural product 4??-O-methylhonokiol (MH) has been shown to prevent amyloidogenesis and progression of AD by inhibiting neuroinflammation. In this commentary we discuss an intriguing link between the recently found CB₂ receptor-mediated molecular mechanisms of MH and its anti-inflammatory and protective effects in AD animal models. We argue that the novel cannabimimetic MH may exert its beneficial effects via modulation of CB₂ receptors expressed in microglial cells and astrocytes. The recent findings provide further evidence for a potential role of CB₂ receptors in the pathophysiology of AD, spurring target validation and drug discovery.     

Effect of IL-18 on IL-1beta and sIL-1RII production by human neutrophils

In the present study we investigated the effect of interleukin 18 (IL-18) on the production of IL-1beta and soluble IL-1 receptor II (sIL-1RII) by human neutrophils. The results obtained indicate that recombinant human IL-18 (rhIL-18) induces IL-1beta and, to a lesser extent, sIL-1RII production by human neutrophil isolated from peripheral blood. However, this effect was less important than lipopolysaccharide (LPS) stimulation. Additionally, our observations suggest that IL-18 can induce priming of neutrophils for IL-1beta and, to a lesser extent, sIL-IRII production by LPS-stimulated cells. The ability of IL-18 to serve as an effective modulator for IL-1beta and its regulatory protein may have significance in the inflammatory and immune reactions mediated by IL-1beta.     

Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia

ABSTRACT: BACKGROUND: The pleiotropic pro-inflammatory cytokine Interleukin (IL)-18 has been proposed to play a role in schizophrenia, since elevated circulating levels of its protein and altered frequencies of genetic variants in its molecular system are reported in schizophrenic patients. METHODS: We analyzed 77 patients with schizophrenia diagnosis (SCZ) and 77 healthy control subjects (HC) for serum concentration of both IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP). RESULTS: We confirmed that serum levels of total IL-18 are significantly increased in SCZ, as compared to HC. However, due to a highly significant increase in levels of circulating IL-18BP in SCZ, as compared to HC, the levels of free, bioactive IL-18 are not significantly different between the two groups. In addition, the relationships between the levels of IL-18 and its inhibitor, as well as between the two molecules and age appear dissimilar for SCZ and HC. In particular, the elevated levels of IL-18BP, likely a consequence of the body's attempt to counteract the early prominent inflammation which characterizes schizophrenia, are maintained in earlier and later stages of the disease. However, the IL-18BP elevation appears ineffective to balance the IL-18 system in younger SCZ patients, while in older patients the levels of circulating bioactive IL-18 are comparable to those of HC, if not lower. CONCLUSIONS: In conclusion, these findings indicate that the IL-18 system is perturbed in schizophrenia, supporting the idea that this pro-inflammatory cytokine might be part of a pathway of genetic and environmental components for vulnerability to the disease.