Department of Internal Medicine, Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
Immunology. 2014 Sep;143(1):68-80. doi: 10.1111/imm.12291.
Human cathelicidin LL-37 protects against infections and endotoxin-induced inflammation. In a recent study we have shown that IG-19, an LL-37-derived peptide, protects in a murine model of arthritis. Cytokine interleukin-32 (IL-32) is elevated and directly associated with the disease severity of inflammatory arthritis. Therefore, in this study we examined the effects of LL-37 and IG-19 on IL-32-induced responses in human peripheral blood-derived mononuclear cells (PBMC) and macrophages. We showed that CD14(+) monocytes are the primary cells that produce pro-inflammatory tumour necrosis factor-α (TNF-α) following stimulation of PBMC with IL-32. We demonstrated that LL-37 and IG-19 significantly suppress IL-32-induced production of pro-inflammatory cytokines, e.g. TNF-α and IL-1β, without altering chemokine production. In contrast, LL-37 and IG-19 enhance the production of the anti-inflammatory cytokine IL-1RA. Further mechanistic studies revealed that LL-37 and IG-19 suppress IL-32-mediated phosphorylation of Fyn (Y420) Src kinase. In contrast, IL-32-mediated phosphorylation of AKT-1 (T308) and MKP-1 (S359) is not suppressed by the peptides. LL-37 and IG-19 alone induce the phosphorylation of MKP-1 (S359), which is a known negative regulator of inflammation. Furthermore, the peptides induce the activity of p44/42 mitogen-activated protein kinase, which is known to phosphorylate MKP-1 (S359). This is the first study to demonstrate the regulation of IL-32-induced inflammation by LL-37 and its derivative peptide IG-19. The mechanistic results from this study suggest that regulation of immune-mediated inflammation by these peptides may be controlled by the dual phosphatase MKP-1. We speculate that LL-37 and its derivatives may contribute to the control of immune-mediated inflammatory diseases.
人源杀菌肽 LL-37 可预防感染和内毒素诱导的炎症。在最近的一项研究中，我们已经表明，IG-19，一种 LL-37 衍生肽，可在关节炎的小鼠模型中发挥保护作用。细胞因子白细胞介素-32（IL-32）升高，并与炎症性关节炎的疾病严重程度直接相关。因此，在这项研究中，我们研究了 LL-37 和 IG-19 对人外周血单核细胞（PBMC）和巨噬细胞中 IL-32 诱导反应的影响。我们发现，CD14(+)单核细胞是在 PBMC 受到 IL-32 刺激后产生促炎性肿瘤坏死因子-α（TNF-α）的主要细胞。我们证明，LL-37 和 IG-19 可显著抑制 IL-32 诱导的促炎性细胞因子（例如 TNF-α和 IL-1β）的产生，而不改变趋化因子的产生。相反，LL-37 和 IG-19 增强抗炎细胞因子 IL-1RA 的产生。进一步的机制研究表明，LL-37 和 IG-19 抑制 IL-32 介导的 Fyn（Y420）Src 激酶的磷酸化。相反，肽不抑制 IL-32 介导的 AKT-1（T308）和 MKP-1（S359）的磷酸化。LL-37 和 IG-19 单独诱导 MKP-1（S359）的磷酸化，MKP-1（S359）是炎症的已知负调节剂。此外，这些肽诱导 p44/42 丝裂原活化蛋白激酶的活性，该激酶已知磷酸化 MKP-1（S359）。这是第一项研究表明 LL-37 及其衍生肽 IG-19 调节 IL-32 诱导的炎症。该研究的机制结果表明，这些肽对免疫介导的炎症的调节可能受到双磷酸酶 MKP-1 的控制。我们推测 LL-37 及其衍生物可能有助于控制免疫介导的炎症性疾病。
