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  • Studies also provide evidence that cytokines such as TGF

    2020-04-17

    Studies also provide evidence that cytokines such as TGF-β, a TH3-type cytokine, may also play a role in airway remodeling. Data obtained by Cohen et al suggest that TGF-β1 can induce human BSMC proliferation by increasing the expression of IGFBP-3. Hence, the Sodium phosphate monobasic mitogenic action of TGF-β1 could be relevant in the hyperplastic nature of BSMC in chronic asthma. In normal human lung, the bronchial epithelial compartment appears to be the main source of TGF-β. The expression levels of this cytokine are dramatically increased in Sodium phosphate monobasic and several other lung disorders.27, 29 The TH2-type cytokine IL-13 is also overexpressed in asthmatic patients. Interestingly, data suggest that both IL-4 and IL-13 cause inflammation, but only IL-13 causes subepithelial fibrosis. The tissue remodeling induced by IL-13 is mediated, to a great extent, by the production and activation of TGF-β1 in lung macrophages.12, 31 Data also support the role of IL-13 in airway remodeling by modulating the production of TGF-β2 from human bronchial epithelial cells. The release of TGF-β2 can activate the underlying myofibroblasts to secrete matrix proteins and smooth muscle mitogens to propagate remodeling changes into the submucosa. Interestingly, IFN-γ reduced the release of TGF-β2 induced by IL-13 in human bronchial epithelial cells.32, 33 Although IL-4 and IL-13 share a common receptor complex of IL-4Ra-IL-13RaI in airway smooth muscle cells and common signaling pathways involving STAT6 and ERK mitogen-activated protein kinase activation,34, 35 IL-4 neither upregulated CysLT1 receptor expression nor synergized with LTD4 for BSMC proliferation, in contrast to IL-13. A differential effect of IL-4 and IL-13 was also reported by Laporte et al in airway smooth muscle cells in which IL-13 but not IL-4 reduced β-adrenergic responsiveness. Conversely, Pype et al found IL-4 to inhibit IL-1b–induced MCP-1 and MCP-2 expression in BSMC, whereas IL-13 did not. Interestingly, gene chip experiments show a distinct although partially overlapping array of genes expressed by BSMC in response to IL-4 and IL-13. Taking all the above data into consideration, it is likely that the smooth muscle proliferation seen in the asthmatic airways is due to a positive feedback interaction between cysLTs and increased levels of TGF-β and IL-13. In our model, the number of receptors for LTD4 was increased by TGF-β and IL-13 (the levels of which are augmented in asthmatic airways). Increased receptor expression could lead to increased LTD4 signaling, resulting in BSMC proliferation. Although such a cytokine-leukotriene synergy could be due to cytokine-upregulated CysLT1 receptor expression, it could also be due to selective interactions between the signaling pathways of IL-13 and TGF-β and LTD4, independent of CysLT1 receptor density. Distinction between the two mechanisms, which are not mutually exclusive, is difficult, but the following findings should also be considered: First, eliminating the preincubation period with IL-13 or TGF-β and adding them at the time of addition of LTD4 abolished the synergy. Second, preincubating with IL-4, which did not upregulate CysLT1 receptor expression, did not result in synergy with LTD4. Since these observations suggest but cannot prove a causal relation between upregulated CysLT1 receptor expression and synergy between cytokines and LTD4 in BSMC proliferation, this relation should be considered as an association rather than a cause and effect, at this time. Although the exact proliferation mechanism is unknown, our data suggest that MAP kinase (ERK) and PI3-kinase pathways may be involved, given that these pathways are the major positive regulators of airway smooth muscle proliferation.38, 39 However, additional experiments are needed to understand the precise mechanisms involved in this process. In conclusion, as illustrated in Fig 6, we demonstrated that TGF-β, IL-13, and IFN-γ but not IL-4 can upregulate the protein expression of CysLT1R in human BSMC.