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Interleukin 17B (IL-17B) is the least known member in IL17 family. However, IL-17B has captured the attention of researches in most field of biology and medicine since it shows pleiotropic functions on a variety of cells.
The biological functions of IL-17B
It has been shown that IL-17B upregulates the expression of IL-6 and granulocyte colony-stimulating factor (G-CSF) induced by tumor necrosis factor α (TNF-α) in the fibroblasts, which is different with IL-17A. Moreover, IL-17B has been found to induce the production of TNF-α and IL-1β but not IL-1α, IL-6, IFN-γ, or G-CSF in monocytic cell line. Additionally, IL-17B is also implicated with the expression of cytokines IL-1α, IL-6, and IL-23 in both the 3T3 cell line and peritoneal exudate cells. Studies have found that intraperitoneal injection of rhIL-17B leads to indirect recruitment of neutrophils to the peritoneal cavity, which might elicit the expression and secretion of chemokines. Furthermore, a recent report has shown that IL-17B induced the migration of CXCR4+ or CXCR5+ germinal center (GC) B cells to CXCL12 and CXCL13 via negative regulating chemokine receptor RGS16. Serval reports have revealed the promotion effect of IL-17B on the expression of IL-8 in human bronchial epithelial cells, which is regulated by multiple signaling pathways including Akt, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-κB). Furthermore, studies have reported that IL-17B might promote the proliferation and migration of tumor via inducing the expression of stemness-related genes Nanog.
IL-17B signaling pathways in related diseases
Recent studies have delved into the actual mechanisms of action of IL-17B on various diseases. It is shown that IL-17B exerts its functions via different signaling pathways in different diseases. Studies have reported that binding of IL-17B to its homodimer receptor (IL17RB) recruits adaptor protein Act1. Furthermore, binding of IL-17RB to Act1 recruits TRAF6, which activates a variety of signaling pathways including NF-κB, p-AKT, ERK, JNK and MAPK. These signaling pathways have been demonstrated to play important roles in various cancer according to accumulating studies. Several studies have reported that amplified signaling IL-17RB/IL-17B in breast cancer cells activates NF-κB to upregulate antiapoptotic factor Bcl-2, promoting breast tumorigenicity and inducing etoposide resistance. Moreover, researches have reported that IL-17B/IL-17RB signal significantly increases the expression of the stemness-related factor (Oct4, Nanog, Lgr5, and Sall4) and the ability of adipogenic differentiation of gastric cancer cells by activating AKT/β-catenin pathway. However, the mechanism of IL-17B upregulating the stemness of gastric cancer cells requires more study. Additionally, studies have demonstrated that IL-17B/IL-17RB activates ERK1/2 pathway to induce the expression of chemokine CCL20, CXCL1, IL-8, trefoil factor 1 (TFF1), promoting cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival in distant organs. Thus IL-17B/IL-17RB might be an effective therapeutic target in these cancers.
Studies have found that IL-17B induces the expression of proinflammatory IL-8 and the activation of NF-κB, which indicates that IL-17B is implicated with inflammation diseases. It is shown that the expression of IL-17B increased in rheumatoid synovial tissue, becoming the predominantly expressed cytokine. These might promote the proliferation and survival of neutrophil and aggravate chronic diseases and tissue destruction eventually. Studies on community-acquired pneumonia have shown that IL-17B induces the expression of IL-8 in gene and protein level via activating signaling pathways such as Akt, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and NF-κB. Furthermore, IL-17B levels are also highly expressed in systemic lupus erythematosus, promoting the expression of TNF-α. This finding indicates IL-17B might be involved in the pathogenesis of the disease. All the studies above have revealed the proinflammatory effect of IL-17B. Thus, further studies on the IL-17B and its related signaling pathways will be contributed to scan the effective therapeutic target in these diseases.
Figure 1. IL-17B signaling pathways and its related diseases.