Allergic asthma reflects an imbalance of pro-and anti-inflammatory components of the immune system,and in asthma patients,endogenous mechanisms that maintain homeostasis in the lung are thought to be defective.IL-10 i...Allergic asthma reflects an imbalance of pro-and anti-inflammatory components of the immune system,and in asthma patients,endogenous mechanisms that maintain homeostasis in the lung are thought to be defective.IL-10 is recognized as an important anti-inflammatory cytokine that suppresses the activity of many innate and adaptive immune cells.Genomic variants in the IL10 locus are associated with increased asthma prevalence in adults,and patients with severe asthma are more likely to have the low IL-10-producing haplotype[3].Accordingly,compared with healthy controls,patients with asthma were reported to have reduced IL-10 levels in bronchoalveolar lavage(BAL)fluid and alveolar macrophages[4].Other groups,however,observed increased or unchanged levels of IL-10 in patients[5,6].The anti-inflammatory function of IL-10 was demonstrated in various mouse models in which eosinophilic airway inflammation was inhibited by exogenous IL-10 and enhanced by IL-10 deficiency[6].In HDM-driven airway inflammation models,IL-10 was shown to exert direct effects on Th2 cells and to improve the balance between regulatory T cells and Th17 cells[7,8].However,it was also reported that IL-10 does not affect eosinophilic inflammation and that IL-10 could promote allergen-induced airway hyperresponsiveness[9,10].Therefore,it can be concluded that data on the role of IL-10 in asthma are rather contradictory,which is likely caused by the nature of the allergen used,allergen dose,and the protocols of sensitization and challenge.The fact that IL-10 is produced by almost every cell type of the immune system makes it even more challenging to unravel its role in allergic airway inflammation.In this issue of Cell.Mol.Immunol.,Qian et al.report a remarkable pro-inflammatory role of B cell-derived IL-10[11].They employ mice that are deficient in Bcl-3,a regulator of NF-κB that was previously linked to the regulation of Il10 gene expression in T lymphocytes[12].In contrast to classical,cytoplasmic IκB family inhibitors,Bcl-3 is present in the nucleus and modulates NF-κB-mediated gene expression by directly contacting NF-κB p50.Qian et al.observed that IL-10 production was elevated in the lungs of Bcl-3−/−mice subjected to HDM-induced allergic airway inflammation compared with Bcl-3+/+mice.Significantly increased infiltration of eosinophils and lymphocytes was found in the BAL fluid of Bcl-3-deficient mice.The levels of the type 2 cytokines IL-4,IL-5,and IL-13 in the lungs and in HDM-restimulated MLN cell cultures were higher in the absence of Bcl-3.Importantly,Bcl-3−/−mice showed considerably increased airway hyperreactivity in response to increasing doses of metacholine.These results support a model in which Bcl-3 protects against HDM-induced allergic asthma.展开更多
文摘Allergic asthma reflects an imbalance of pro-and anti-inflammatory components of the immune system,and in asthma patients,endogenous mechanisms that maintain homeostasis in the lung are thought to be defective.IL-10 is recognized as an important anti-inflammatory cytokine that suppresses the activity of many innate and adaptive immune cells.Genomic variants in the IL10 locus are associated with increased asthma prevalence in adults,and patients with severe asthma are more likely to have the low IL-10-producing haplotype[3].Accordingly,compared with healthy controls,patients with asthma were reported to have reduced IL-10 levels in bronchoalveolar lavage(BAL)fluid and alveolar macrophages[4].Other groups,however,observed increased or unchanged levels of IL-10 in patients[5,6].The anti-inflammatory function of IL-10 was demonstrated in various mouse models in which eosinophilic airway inflammation was inhibited by exogenous IL-10 and enhanced by IL-10 deficiency[6].In HDM-driven airway inflammation models,IL-10 was shown to exert direct effects on Th2 cells and to improve the balance between regulatory T cells and Th17 cells[7,8].However,it was also reported that IL-10 does not affect eosinophilic inflammation and that IL-10 could promote allergen-induced airway hyperresponsiveness[9,10].Therefore,it can be concluded that data on the role of IL-10 in asthma are rather contradictory,which is likely caused by the nature of the allergen used,allergen dose,and the protocols of sensitization and challenge.The fact that IL-10 is produced by almost every cell type of the immune system makes it even more challenging to unravel its role in allergic airway inflammation.In this issue of Cell.Mol.Immunol.,Qian et al.report a remarkable pro-inflammatory role of B cell-derived IL-10[11].They employ mice that are deficient in Bcl-3,a regulator of NF-κB that was previously linked to the regulation of Il10 gene expression in T lymphocytes[12].In contrast to classical,cytoplasmic IκB family inhibitors,Bcl-3 is present in the nucleus and modulates NF-κB-mediated gene expression by directly contacting NF-κB p50.Qian et al.observed that IL-10 production was elevated in the lungs of Bcl-3−/−mice subjected to HDM-induced allergic airway inflammation compared with Bcl-3+/+mice.Significantly increased infiltration of eosinophils and lymphocytes was found in the BAL fluid of Bcl-3-deficient mice.The levels of the type 2 cytokines IL-4,IL-5,and IL-13 in the lungs and in HDM-restimulated MLN cell cultures were higher in the absence of Bcl-3.Importantly,Bcl-3−/−mice showed considerably increased airway hyperreactivity in response to increasing doses of metacholine.These results support a model in which Bcl-3 protects against HDM-induced allergic asthma.
