Tulobuterol inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells

Abstract

A transdermal patch preparation of the β2 agonist tulobuterol has been designed to yield sustained β2 agonistic effects and has been used as a long-acting β2 agonist (LABA) in Japan. LABAs reduce the frequency of exacerbations of chronic obstructive pulmonary disease and bronchial asthma. However, inhibitory effects of LABAs on the replication of rhinovirus (RV), the major cause of exacerbations, have not been demonstrated. To examine the effects of tulobuterol on RV replication and on the production of the replication-induced pro-inflammatory cytokines, human tracheal epithelial cells were infected with a major group RV, type 14 rhinovirus (RV14). Tulobuterol reduced the RV14 titers and RNA levels; the concentrations of cytokines, including interleukin (IL)-1β, IL-6, and IL-8, in the supernatants; and susceptibility to RV14 infection. Tulobuterol reduced the expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for RV14, and the number of acidic endosomes in the cells in which RV14 RNA enters the cytoplasm. Tulobuterol inhibited the activation of nuclear factor kappa B (NF-κB) proteins in nuclear extracts. A selective β2-adrenergic receptor antagonist, ICI 118551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol], reversed the inhibitory effects of tulobuterol on the RV14 titers and RNA levels, the susceptibility to RV14 infection, cytokine production, and ICAM-1 expression. Tulobuterol may inhibit RV replication by reducing ICAM-1 expression and acidic endosomes and modulate airway inflammation during RV replication.

Formoterol and budesonide inhibit rhinovirus infection and cytokine production in primary cultures of human tracheal epithelial cells

“…cAMP increases endosomal pH by inhibiting an Na þ /H þ exchanger [29]. We demonstrated that formoterol increased the cAMP levels in HNE cells, which decreased the number of acidic endosomes, as previously reported for HTE cells [30]. Therefore, formoterol may inhibit the functioning of Na þ /H þ exchangers via the production of cAMP in cells.…”

β2-Adrenergic receptors in immunity and inflammation: Stressing NF-κB

“…Several reports showed that b 2 -AR stimulation mitigates NF-jB phosphorylation, nuclear translocation, DNA binding and transcriptional activity, in both immune (Farmer and Pugin, 2000;Herve et al, 2013;Hu et al, 2012;Loop et al, 2004;Loza et al, 2006;Mortaz et al, 2008;Strell et al, 2009;Yang et al, 2003) and non-immune cell types (Baouz et al, 2005;Yamaya et al, 2013) (For details refer to Table 1). In many cases NF-jB activity was measured via electrophoretic mobility shift assay (EMSA), which assesses DNA binding, or using microscopy to image NFjB localisation in the cell.…”

Increased rhinovirus replication in nasal mucosa cells in allergic subjects is associated with increased ICAM‐1 levels and endosomal acidification and is inhibited by L‐carbocisteine

“…However, a number of other drugs, including inhaled steroids, β 2 agonists and leukotriene receptor antagonists, also reduce asthma exacerbations . Furthermore, inhaled steroids and β 2 agonists inhibit RV replication and the RV infection‐induced production of cytokines, as we previously reported . Therefore, careful attention is needed when considering the influence of the effects of these drugs in evaluations of the ability of L‐carbocisteine to prevent asthma exacerbation.…”