IL-9: Allergic Disease Drug Target in Cytokines & Growth factors

Introduction of IL-9 as a Cytokine

IL-9, similarly to many cytokines, is pleiotropic in function. On haematopoietic cells, IL-9 signals through a specific IL-9 receptor chain (IL-9Rα) and the common γ-chain (γc; also known as IL-2Rγ), which is shared with the receptors for related cytokines including IL-2, IL-4 and IL-21. IL-9 promotes mast cell and T cell growth, stimulates mast cell accumulation in tissues, promotes innate lymphoid cells survival, enhances class-switching to IgE in B cells and alters haematopoietic progenitor cell activity. Although some in vivo IL-9 functions require TH2-type cytokine production, IL-9 can promote the differentiation of IL-17-secreting cells in vitro. IL-9Rα is also expressed on non-haematopoietic cells, including on airway and intestinal epithelial cells, smooth muscle cells and keratinocytes.

The Role of Drug Target IL-9 in Allergic Disease

1) IL-9 was originally described as a mast cell growth factor for its ability to enhance the survival of primary mast cells and to induce their production of the inflammatory cytokine IL-6. IL-9 also stimulates the production of mast cell proteases and the high-affinity IgE receptor (FceRIa), suggesting that IL-9 primes mast cells to respond to allergen via increased cell surface expression of the high-affinity IgE receptor and the production of inflammatory mediators including IL-6 and several proteases. ) IL-9 was cloned as a T-cell growth factor for its ability to support antigen-independent growth of T helper clones. Expression studies in vitro show that IL-9 could be produced by TH2-type lymphocytes, making it a member of the TH2 cytokine family. 3) In addition, studies of immunoglobulin production in vitro by B cells demonstrated that IL-9 enhances the IL-4-mediated production of IgE in human and murine B cells. 4) Recently, IL-9 has been shown to promote eosinophil maturation in synergy with IL-5. IL-9 modulates the expression of IL-5Ra in myeloid precursor cell lines. IL-9 might therefore induce airway eosinophilia through the upregulation of IL-5 response and potentiating the IL-5-mediated maturation of eosinophil precursors. 6) Furthermore, IL-9 has been shown to activate airway epithelial cells by stimulating the production of several chemokines, proteases, ion channels and selective mucin genes. Longphre et al concluded, on the basis of studies in vitro and in vivo, that IL-9, but not IL-5 or IL-13, might account for most of the mucin-stimulatory activity of lung fluids in allergic airway disease. Taken together, these results indicate that IL-9 has pleiotropic activities on various cell types that are important in the pathogenesis of asthma. It is noteworthy that, unlike the IL-4-mediated production of IgE by B cells, or the IL-5-induced maturation of eosinophils, IL-9 seems to act primarily by enhancing the activities of many other cytokines and factors. Blockage of its activity is therefore less likely to compromise normal host defense.

Targeting IL-9 in Allergic Disease Therapy

Two studies using IL-9 neutralizing antibody confirmed that IL-9 is a necessary mediator of asthma. In one of the models, IL-9-neutralizing antibody was instilled directly into the lungs of mice exposed to either Aspergillus fumigatus or dust mite antigen. In these asthma models of mucosal TH2 immunity, A. fumigatus or dust mite antigen produced a marked allergic inflammatory response in (B6D2)F1 mice, including significant increases in BAL eosinophils, elevated serum total IgE, increased mucin production, and AHR in comparison with control or naive animals. Intratracheal administration of IL-9-neutralizing antibody reduced the constellation of allergic inflammation in these models including AHR, serum total IgE elevations, and increases in BAL eosinophils in comparison with treatments of isotype-specific control antibody or untreated sensitized mice. Alcian Blue/PAS stains for mucus and overall histopathologic grading confirmed that the antibody treatment effectively abrogated the allergic asthmatic response in the antigen-challenged animals. An independent study showed that similar blockage results from systematic administration of an IL-9 neutralization antibody in ovalbumin-treated BALB/c mice. Taken together, these results demonstrate that IL-9 is both necessary and
sufficient to produce the asthmatic response.

IL-9 as Drug Target in Allergic Disease: Conclusion

Cell biology in vitro has shown that IL-9 is an important growth factor and stimulator of numerous cell types important in the pathogenesis of asthma. Mice overexpressing IL-9 and neutralizing antibodies further demonstrate a crucial role for IL-9 in the development of the allergic asthmatic response. Importantly, increased lung IL-9 expression in mice and humans is tightly and specifically associated with asthma and its risk factors; decreased IL-9 is protective from antigen challenge. IL-9-deficient animals, including naturally occurring mutants and transgenic knockout mice, are healthy, suggesting that IL-9 therapeutic intervention will be well tolerated. Thus, IL-9 seems to be both necessary and sufficient to produce the TH2 response in vivo and is an important therapeutic target for allergic asthma.

IL-9: Allergic Disease Drug Target in Cytokines & Growth factors Reference

Zhou Y, et al. Th2 cytokines and asthma—Interleukin-9 as a therapeutic target for asthma[J]. Respiratory research, 2001, 2(2): 80.