Xiaobao Jin

IL-33 prolongs murine cardiac allograft survival through induction of TH2-type immune deviation.

Background. In Th (T helper) 1/Th2 balance in response to signals given during donor antigen presentation, induction of allograft prolongation is more often related to Th2-type than with Th1-type immunity. Here, we examined the effect of interleukin (IL)-33, a novel member of the IL-1 family, on cardiac allograft survival in mice. Methods. Mice heterotopic cardiac transplants were performed with sequential recipient sacrifice at anticipated time points to examine the immunoregulatory action of IL-33 in recipient mice. Results. In vitro Th1-polarized CD4+ T cells did not express ST2L; however, most CD4+ T cells became ST2L+ on repeated stimulation under Th2-polarizing conditions. Similarly, we found that IL-33 was able to enhance the expression of Th2-associated cytokines (IL-5 and IL-13) but not interferon (IFN)-&ggr;. Treatment of recipient mice with IL-33 results in the improvement of allograft survival (more than 20 days) when compared with phosphate-buffered saline- or glutathione S-transferase-treated groups (all less than 9 days). Intracellular cytokine staining in CD4+ splenocytes confirmed an increase in the percentage of IL-4+ cells and a decrease in the percentage of IFN-&ggr;+ cells in IL-33 treated mice. In addition, IL-33 significantly enhanced the gene expression of Th2-type cytokines IL-4 and IL-5 but suppressed the Th1-type cytokine IFN-&ggr; mRNA levels in both allograft and recipient spleen. Conclusion. These data demonstrate that IL-33 serves as a potent inducer of Th2 immune response and can markedly contribute to the prolongation of cardiac allograft survival.

Adenovirus-mediated overexpression of soluble ST2 provides a protective effect on lipopolysaccharide-induced acute lung injury in mice

Acute lung injury is characterized by a diffuse inflammatory parenchymal process, implicated in the context of significant morbidity and mortality. Previously, we have reported that soluble ST2 (sST2), a member of the Toll‐interleukin (IL)‐1 receptor (TIR) superfamily, represses proinflammatory cytokine production of macrophage exposed to lipopolysaccharide (LPS). In this study, we examined the possibility of modulating LPS‐induced murine inflammatory pulmonary damage by recombinant adenovirus‐mediated sST2‐Fc (Ad‐sST2‐Fc) gene transfer. Single intranasal administration of Ad‐sST2‐Fc led to a profound decrease in LPS‐induced bronchoalveolar lavage leucocyte exudation and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Histological examination revealed alveolitis with inflammatory cell infiltration and alveolar haemorrhage in the alveolar airspace was less severe in Ad‐sST2‐Fc‐treated mice when compared with control groups. In addition, high levels of sST2‐Fc in vivo reduced the transcription of tumour necrosis factor‐α, IL‐6 and Toll‐like receptor‐4 gene remarkably, and suppressed the nuclear translocation of nuclear factor‐κB in lung tissues in response to LPS challenge. Taken together, these results suggested that administration of Ad‐sST2‐Fc gene transfer may have therapeutic potential for the immunomodulatory treatment of LPS‐mediated inflammatory lung injury.

Adenovirus-mediated delivery of soluble ST2 attenuates ovalbumin-induced allergic asthma in mice.

Allergic asthma is associated with excessive T helper type 2 (Th2) cells activation and airway hyperreactivity (AHR), implicated in the context of significant morbidity and mortality. Soluble ST2, a member of the interleukin (IL)‐1 receptor family, has been shown to play a critical role in modulation of inflammatory disorders, yet the function of soluble ST2 in allergic inflammation remains unclear. In this study, we examined the possibility of regulating ovalbumin (OVA)‐challenged airway inflammation by recombinant adenovirus‐mediated sST2‐Fc (Ad‐sST2‐Fc) gene transfer. Single intranasal administration of Ad‐sST2‐Fc before allergen challenge in OVA‐immunized mice profoundly reduced serum immunoglobulin (Ig)E secretion, eosinophil infiltration and concentrations of IL‐4, IL‐5 and IL‐13 in bronchoalveolar lavage fluid compared with administration of a control Ad vector. Histopathological examination of the lungs revealed that sST2‐Fc over‐expression markedly suppressed allergen‐induced peribronchial inflammation and disruption of the alveolar architecture. Moreover, the beneficial effect of sST2‐Fc in allergic lung inflammation is related to blocking the IL–33/ST2L signalling. Taken together, these results suggested that administration of Ad‐sST2‐Fc gene transfer may have therapeutic potential for the immunomodulatory treatment of OVA‐mediated allergic pulmonary diseases.

Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor

Although studies have demonstrated that heme oxygenase-1 (HO-1) prevents leukocyte infiltration and organ damage following LPS challenge, the mechanisms involved in this protection are incompletely understood. Macrophage migration inhibitory factor (MIF) is thought to play a pivotal role in modulation of inflammatory and immune response through upregulation of TLR4 expression. Activation of TLR4 results in the production of proinflammatory mediators including MIF, which induce neutrophils recruitment and subsequent tissue insults. We hypothesized that HO-1 mediates its salutary effects in lipopolysaccharide (LPS)-induced inflammatory lung injury via downregulation of MIF through modulation of TLR4-induced proinflammatory mediator production. Compared with wild-type cells, MIF-knockdown macrophages in vitro are hyporesponsive to LPS stimulation, as shown by a profound reduction in TLR4 expression and TNF-alpha production. In the murine model of LPS-induced acute lung injury, administration of CoPP, a potent HO-1 inducer, leaded to a significant reduction in LPS-induced pulmonary edema, leucocytes influx, myeloperoxidase activity as well as histopathologic insults. Most strikingly, pretreatment with CoPP markedly decreased the expression of TLR4 and MIF in lung tissues in response to LPS challenge. These findings herein suggest that the cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response.

Heme oxygenase-1 ameliorates LPS-induced acute lung injury correlated with downregulation of interleukin-33

Although studies have shown that heme oxygenase-1 (HO-1) can abrogate leukocyte recruitment and tissue injury after LPS stimulation, the underlying mechanisms remain incompletely understood. Interleukin (IL)-33, a new member of the IL-1 family, is found to play a crucial immunoregulatory effect on the MD2/TLR4 complex expression. Moreover, TLR4 further promotes the activation of NF-κB and the production of proinflammatory mediators, which exacerbate neutrophil infiltration and organ damage. The present study was designed to determine whether the protection of HO-1 against LPS-induced acute lung injury (ALI) is involved in downregulation of IL-33. We observed that the levels of IL-33 mRNA and protein in LPS-stimulated macrophages were strongly suppressed by a potent HO-1 inducer, CoPP, treatment. Meanwhile, CoPP significantly reduced the expression of TLR4 and TNF-α in IL-33-pretreated macrophages followed LPS challenge. In the murine model of LPS-induced ALI, CoPP treatment resulted in a remarkable decrease in LPS-mediated leukocyte exudation, Evans blue dye albumin (EBA) leakage as well as histopathologic disruption. Notably, CoPP treatment markedly inhibited the expression of IL-33 and TLR4 in lung tissues under LPS stimulation. Therefore, these data suggest that the cytoprotection of HO-1 in LPS-induced pulmonary injury is associated with negative regulation of IL-33 and TLR4-mediated inflammatory response.

Sphingosine-1-phosphate receptor 1 agonist SEW2871 prolongs heterotopic heart allograft survival in mice

Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune cell trafficking. Recent studies have revealed immunomodulatory functions of S1P and its receptors (S1PR1-S1PR5) in many inflammatory conditions, such as asthma and autoimmunity. Here, we explore the efficacy of SEW2871, a selective S1PR1 agonist, in the prevention of acute allograft rejection in a murine cardiac transplantation model. Treatment of recipient mice with SEW2871 significantly prolongs cardiac allograft survival as compared to those recipients treated with control vehicle. The enhanced graft survival is associated with reduced circulating lymphocytes and allograft inflammatory cell infiltration. The cytokine analysis showed decreased allograft expression of TNF-α, IFN-γ and IL-2 in the SEW2871-treated mice. Moreover, administration of SEW2871 increases the percentage of CD4(+) T regulatory cells and FoxP3 expression in spleen of allograft recipients. Therefore, SEW2871 plays a critical role in regulation of lymphocyte trafficking and development, which directly contributes to prolongation of the allograft survival.