IL-9 and Lung Fibrosis: A Th2 Good Guy?

Interleukin (IL)-9 is a cytokine with pleiotropic activities that has been implicated in the pathogenesis of asthma and is shown in the article by Arras and colleagues as having the capacity to modulate the development lung fibrosis. IL-9 was discovered independently as a growth factor for activated T cells (1) and subsequently for mast cells (2). Cloning of the mouse (3) and human (4) IL-9 cDNAs revealed that they encoded polypeptides 144 amino acids in length which were cleaved to form the secreted proteins of 126 amino acid residues. IL-9 binds to a receptor of the cytokine receptor superfamily that is present on mast cells, macrophages, and subsets of T and B lymphocytes. IL-9 is produced primarily by helper T lymphocytes (5) and has diverse activities that are consistent with the fact that its receptor is expressed on multiple cell types. Freshly isolated T cells generally do not respond to IL-9, but activation or continued passaging results in IL-9 receptor expression so that these cells can proliferate in response to IL-9 (6). IL-9 has been implicated in the development of T-cell lymphomas, since transgenic mice overexpressing IL-9 were prone to develop this type of tumor (7) and T cell lines transfected with IL-9 were tumorigenic in wild-type mice (8). IL-9 synergizes with IL-3 to induce mast cell proliferation (9) and also with IL-4 to stimulate the production of IgE and IgG by B lymphocytes (10). IL-9 also stimulates the proliferation of hematopoietic progenitor cells (11). Further insight into the activities of IL-9 in vivo has been gained from studies in which IL-9 was systemically overexpressed in transgenic mice. These mice, which are designated Tg5, carry an IL-9 transgene under control of a hybrid promoter containing sequences from the pim-1 promoter, E m enhancer, and mMLV LTR (7). These promoter sequences were designed to target IL-9 expression preferentially to T lymphocytes, but in Tg5 mice, IL-9 was found to be expressed in all organs examined and accumulated to very high levels ( . 1 m g/ml) in serum. IL-9 transgenic mice spontaneously developed thymic lymphomas and exhibited increased susceptibility to chemically induced lymphomas. Tg5 mice displayed increased numbers of mast cells in the gastrointestinal and respiratory tracts and kidneys (12). Tg5 mice also exhibited increased numbers of circulating B cells, particularly of the B-1 class. In addition, serum immunoglobulin levels were elevated, with IgG1 and IgE being most pronounced (13). Interest in the action of IL-9 in the lung was stimulated by genetic linkage studies that implicated IL-9 as a candidate gene influencing asthma in humans (14) and airway reactivity in inbred strains of mice (15). Examination of the lungs of Tg5 transgenic mice revealed the presence of eosinophils and constitutive expression of CC chemokines such as eotaxin in lung lavage fluid (16). Tg5 mice also exhibited extensive mucus production in airway epithelial cells (17). Following sensitization and pulmonary challenge with allergen, Tg5 mice displayed increases in serum IgE levels, pulmonary eosinophilic inflammation, and airway hyperreactivity compared to nontransgenic mice (18). Targeted expression of an IL-9 transgene specifically to the lungs of mice has been achieved using the airway epithelial-specific CC10 promoter (19). These mice in the absence of allergic sensitization displayed many features characteristic of asthma, including eosinophilic inflammation, airway hyperreactivity, increased numbers of mast cells in the airway epithelium, mucous cell metaplasia, and airway fibrosis. These studies, along with the detection of elevated IL-9 levels in the lungs of asthmatics (20), suggest that IL-9 may be an important mediator in the pathophysiology of asthma. IL-9 belongs to a group of cytokines produced by lymphocytes of the Th2 class. CD4 T cells have been classified into subsets designated Th1 and Th2 based on their distinct cytokine profiles. Th1 cells are induced by most intracellular pathogens, mediate cytotoxicity and delayed-type hypersensitivity reactions, and secrete interferong (IFNg ), IL-12, and IL-18. IFNg and IL-12 are important for the development of the Th1 response, and IFNg inhibits the development of Th2 cells. Th2 cells are typically induced by parasitic infections, are involved in allergic immune responses and asthma, and produce IL-4, IL-5, IL-9, IL-10, and IL-13. IL-4 appears to act early in Th2 cell development to induce the Th2 phenotype, and IL-10 serves to inhibit the development of Th1 cells. Immune responses in which Th1 or Th2 cells and cytokines predominate have been termed type 1 and type 2 responses, respectively. In addition to distinct cytokine profiles, type 1 and type 2 immune responses exhibit production of characteristic immunoglobulin subtypes: IgG2a for Th1, and IgE and IgG1 for Th2. ( Received in original form February 23, 2001 )