The Role of Interleukin-9 in Cancer
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REVIEW
The Role of Interleukin-9 in Cancer Jacob E. Lee 1 & Ziwen Zhu 2 & Qian Bai 2 & Tucker J. Brady 1 & Huaping Xiao 1,3 & Mark R. Wakefield 2 & Yujiang Fang 1,2 Received: 21 January 2019 / Accepted: 12 April 2019 # Arányi Lajos Foundation 2019
Abstract Interluekin-9 (IL-9) is produced predominantly by helper T cells such as Th2 and Th9 cells. It normally functions through the activation of a JAK/STAT pathway and plays a critical role in immunity and the pathogenesis of cancer. In cancer, it yields different responses depending on the cancer cell line involved. This review is a summary of what is known about the involvement of IL-9 in various cancer cell lines as well as its role in immunity with a focus on allergic responses. Keywords Interleukin 9 . Cancer . Inflammation
Introduction Human interleukin-9 (IL-9) was first identified in the late 1980s. Its gene is located on the long arm of chromosome 5. The IL-9 protein has 144 amino acid residues with a signal peptide of 18 amino acid residues. IL-9 is mainly secreted by Th2, Th9, and mast cells although many other cells could secret IL-9, such as Th17 cells, Tregs, CD8+ T cells, innate lymphoid cells, NKT cells, and dendritic cells [1–10]. IL-9 production may be promoted by IL-1β, IL-2, IL-4, IL6, IL-9, IL-10, IL-12, IL-21, IL-25, IL-33, TGF-B, TSLP (thymic stromal lymphopoietin), and transcription factor PU.1 [11–21]. IFN-g represents a potential inhibitor for IL-9 expression [11, 12]. IL-9 signals through the IL-9 receptor and this receptor is composed of two subunits: IL-9Rα (IL-9–specific alphachain) and γc (the common γ-chain) which is also a subunit of the IL-2, IL-4, IL-7, IL-15 and IL-21 receptors [22, 23]. IL-9Rα is constitutively bound to JAK1 and the γc is constitutively bound to JAK3 [24]. The IL-9Rα can sufficiently bind IL-9 on its own but cannot mediate the signal * Yujiang Fang [email protected] 1
Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, Iowa 50312, USA
2
Department of Surgery, University of Missouri School of Medicine, Columbia, MO, USA
3
The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
any further without the γc portion [25]. Upon the receptor ligation, a juxtaposition occurs between the 2 chains. This results in auto and or trans phosphorylation of JAK kinases. Specifically, there exists a proline rich box-1 region in the cytoplasmic domain of IL-9Rα, which is required for JAK binding and activation and mediates STAT phosphorylation [26]. The Tyrosine 407 residue is the cytoplasmic part of IL-9Rα phosphorylated upon ligand binding, and is the docking site for STAT −1, −3, and − 5 transcription factors. This residue is required for STAT transcription factor activation [24]. The phosphorylated STAT molecules dimerize and migrate to the nucleus, where they bind regulatory sequences for de novo gene expression and thus links IL-9 to its pleiotropic biological functions. IL-9 is a pleiotropic cytokine that has both direct and indirect e
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