Munitz Ariel, Seidu Luqman, Cole Eric T, Ahrens Richard, Hogan Simon P, Rothenberg Marc E
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
J Immunol. 2009 Feb 15;182(4):2357-63. doi: 10.4049/jimmunol.0803130.
Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-alpha at baseline and following an experimental model of colitis. Relm-alpha was readily detected in the serum at baseline (4-5 ng/ml), and its level was regulated by energy uptake. Retnla(-/-) mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla(-/-) mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha was up-regulated, and DSS-treated Retnla(-/-) mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla(-/-) mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.
抵抗素样分子α（Relm-α）是一种分泌型富含半胱氨酸的蛋白质，属于一个新定义的蛋白质家族，该家族包括抵抗素、Relm-β和Relm-γ。抵抗素最初是根据其胰岛素抵抗活性来定义的，但该家族成员在各种炎症状态下，尤其是涉及肠道炎症的状态下高度上调。在本研究中，我们报告了Relm-α在基线时以及在结肠炎实验模型后的作用。在基线时血清中很容易检测到Relm-α（4-5 ng/ml），其水平受能量摄取调节。Retnla(-/-)小鼠的基线循环瘦素水平降低，但血糖、葡萄糖清除率和胰岛素水平正常。在口服先天性触发剂葡聚糖硫酸钠（DSS）后，发现Relm-α具有非冗余的促炎作用，因为Retnla(-/-)小鼠明显受到保护，免受DSS诱导的疾病活动和组织病理学特征的影响。Relm-α在体外调节嗜酸性粒细胞导向的细胞因子（如IL-5、CCL11/嗜酸性粒细胞趋化因子-1和CCL5/调节激活正常T细胞表达和分泌因子）和IL-17。一致地，DSS处理的Retnla(-/-)小鼠显示嗜酸性粒细胞积聚显著减少，巨噬细胞和嗜酸性粒细胞中NF-κB、ERK1/2和p38的磷酸化减少。DSS暴露后，Relm-α的血清水平上调，DSS处理的Retnla(-/-)小鼠明显受到保护，免受葡萄糖注射诱导的高血糖影响，且与胰岛素水平变化无关。Retnla(-/-)小鼠免受DSS处理后诱导的胃抑制多肽和肽YY肠道激素血清水平升高的影响。这些发现证明Relm-α在结肠炎症调节中具有核心促炎作用，以及结肠损伤、葡萄糖耐量和能量摄入之间的新联系。
