Human airway smooth muscle promotes eosinophil differentiation
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INTRODUCTION: Human airway smooth muscle (HASM) cells in culture synthesize cytokines and chemokines that may orchestrate the tissue homing and in situ differentiation of haemopoietic progenitor cells from the peripheral circulation. OBJECTIVE: To study the effect of a supernatant from cultured HASM cells on the differentiative and transmigrational responses of haemopoietic progenitor cells. METHODS: HASM cells were grown to confluence and stimulated with a cytomix of TNF-alpha, IL-1beta and IFN-gamma. Peripheral blood-derived progenitors from atopic asthmatics (n=12) and non-atopic controls (n=11) were grown in a methylcellulose culture with a supernatant from stimulated HASM cells to assess clonogenic potential. The ability of HASM cells to stimulate directional migration and adhesion to fibronectin of blood progenitors was also investigated. RESULTS: HASM cells stimulated significant growth of eosinophil/basophil colony forming units (Eo/B CFUs) from blood progenitor cells from both groups of subjects. This activity was significantly attenuated in the presence of anti-IL-5 and anti-granulocyte macrophage-colony forming factor blocking antibodies and by pre-treatment with SB202190 [p38 mitogen-activated protein kinase (MAPK) inhibitor]. An src kinase (srcK) inhibitor (Pyrazolopyrimidine 1) was less effective at attenuating IL-5- and HASM-stimulated Eo/B CFU growth from both groups of subjects. Examination of the phosphorylation of these kinases in CD34(+) cells following co-incubation with the major constituents of HASM showed activation of p38 MAPK but not that of the srcK pathway. The HASM supernatant had no significant effect on the migrational and adhesive responses of haemopoietic progenitor cells in vitro. CONCLUSION: We have shown that HASM cell-derived cytokines promote eosinophil differentiation that is dependent on p38 MAPK but not on the srcK pathway. This study shows that a major structural cell of the lungs, airway smooth muscle, has the capability to direct eosinophil differentiation and maturation from progenitor cells, which in turn may perpetuate an eosinophilic inflammation and consequently tissue remodelling in patients with chronic asthma.
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