Background <p>Numerous in vivo studies have demonstrated beta-2-adrenoceptor (β₂AR) -agonism as permissive in the development of allergic lung inflammation, and have implicated the arrestin-dependent signaling arm of the β₂AR in mediating this effect. However, the specific cell type(s) mediating β₂AR regulation of allergic lung inflammation remain unestablished.</p> Methods <p>To explore the potential contribution of airway epithelia in this phenomenon, we compared the ability of ractopamine (RP), recently identified as a Gs-biased beta-agonist, to that of the unbiased/balanced beta-agonist albuterol (ALB), on IL-13-stimulated mucin and cytokine production in human airway epithelia cultures in air–liquid interface (HAE). Results: ALB, which activates both the β₂AR-arrestin and -Gs signaling pathways significantly augmented IL-13-induced mucin production in HAE. RP, which preferentially signals via Gs/PKA, did not. Although IL-13 stimulated production of numerous cytokines, including IL-1α, IL-1RA, MDC, TGF-α, and GROα, ALB-mediated augmentation of these cytokines was highly variable and not statistically significant. Similarly, RP did not augment the induction of cytokines stimulated by IL-13. Moreover, in contrast to previous studies that reported a requirement of concomitant β₂AR agonism for IL-13 to stimulate cytokine production, such a requirement was observed only in minority of the (12) cultures examined.</p> Conclusions <p>These data implicate arrestin-dependent β₂AR signaling augmenting airway epithelial mucin production as a contributor to the previously-demonstrated pro-inflammatory effects of β₂AR agonism in vivo. Moreover, they suggest that beta-agonist effects on the cytokine profile in the allergen-inflamed lung may be influenced by specific asthmatic endotypes and involve cooperativity among multiple cell types.</p>