The Regulation and Function of the TSLP Receptor in the Airway Epithelium (36.15)

Abstract Epithelial cells of the airway and lung have been shown to participate actively in the response to both pathogenic and allergenic environmental stimuli. In particular, the airway epithelium is a potent source of thymic stromal lymphopoetin (TSLP), a cytokine that is strongly associated with asthma and other atopic pathogenesis. In the lung, TSLP acting in concert with an antigenic stimulus is capable of inducing hallmarks of the asthmatic response: eosinophilia and inflammatory cell infiltrates, sub-epithelial fibrosis, goblet cell hyperplasia and mucus production, airway hyperresponsiveness, and Th2 cytokine and chemokine production. TSLP production by airway epithelial cells is known to be NF-κ B dependent. Surprisingly, we have found that factors known to upregulate TSLP is also capable of upregulating the heterodimeric TSLP receptor. Stimulation with either TNF-α or infection with Sendai virus results in the upregulation of both TSLPR and IL7R on a human airway epithelial cell line as well as primary murine airway epithelium. These same stimulatory conditions, in combination with the Th2 cytokine IL-4, furthermore result in the upregulation of TARC and CXCL5, chemokines associated with airway inflammation. Upregulation of these chemokines can be inhibited by the addition of an anti-TSLP monoclonal antibody, indicating a role for TSLP signaling in the expression of these genes by the airway epithelium.