In the context of cancer, many studies have reported pro-tumor effects of IL-9 on hematological tumors and solid tumors ( 20, 21). Besides the gathering evidence of proinflammatory functions of IL-9, early studies also showed the effect of IL-9 in inducing immune tolerance in tolerant allografts and in inflammatory disease models ( 18, 19). IL-9 contributes to the pathophysiology of allergic diseases like food allergy, dermatitis or asthma through its autocrine or paracrine effect on T cells, B cells, innate lymphoid cells, mast cells, eosinophils, and neutrophils ( 12, 13, 14, 15, 16, 17). However, there are also somewhat conflicting reports in which IL-9 was found to suppress experimental autoimmune encephalomyelitis (EAE) in mice ( 10, 11). IL-9 has been reported to induce the development of a number of autoimmune diseases such as inflammatory bowel diseases (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) ( 7, 8, 9). Proinflammatory cytokines play important roles in the interaction between innate and adaptive immune cells. The MAP kinase pathway also contributes to the extent IL-9 signaling in several lymphoid and hematopoietic cells lines ( 6).Īlthough the innate and adaptive components of the immune system are 2 arms of the host responses, they work together intimately to induce effective immune responses. In various hematopoietic cells, JAK kinases also mediate the phosphorylation of IRS1/2 which in turn, activates PI3K signaling pathways to induce cell proliferation and prevent caspase-mediated apoptosis ( 4, 5). The activation of STAT family including STAT1, STAT3, and/or STAT5 is crucial for IL-9 to mediate its anti-apoptotic and growth regulatory effects ( 4). In turn, the phosphorylation of tyrosine residues induces activation of transcription factors belonging to the STAT family, insulin receptor substrates (IRSs), and MAP kinase pathway ( 4).
Phosphorylated JAK1 and JAK3 then mediate the phosphorylation of receptor tyrosine residues ( 4). Binding of IL-9 to the ligand-binding subunit IL-9Rα results in formation of the IL-9R heterocomplex, which undergoes a conformational change to allow binding of JAK1 and JAK3. The IL-9 receptor complex consists of the cytokine-specific IL-9 receptor α-chain (IL-9Rα) and the γc-chain ( 2) and therefore IL-9 is a member of the common γc receptor family which includes IL-2, IL-4, IL-7, IL-15, and IL-21 ( 3). Intriguingly, murine IL-9 can function on human cells, but human IL-9 is inactive on mouse cells. The Il9 gene loci of both human and mouse shares 55% amino acid homology at the protein level ( 2). Unlike other growth factors of T cells, IL-9 did not stimulate the proliferation of cytotoxic T cells (Tc) ( 1).
IL-9 was first found to support the long-term growth of antigen-independent Th cell lines ( 1). Without N-linked glycosylation IL-9 is 14 kDa. IL-9, initially termed P40, is a single chain glycoprotein with molecular weight between 32 and 39 kDa ( 1).
0 kommentar(er)
