Autocrine cytokine signaling mediates effects of rhinovirus on airway responsiveness

Abstract

The airway responses to allergen exposure in allergic asthma are qualitatively similar to those elicited by specific viral respiratory pathogens, most notably rhinovirus (RV), suggesting that the altered airway responsiveness seen in allergic asthma and that elicited by viral respiratory tract infection may share a common underlying mechanism. To the extent that T helper cell type 2 (Th2) cytokines have been implicated in the pathogenesis of allergic asthma, this study examined the potential role(s) of Th2-type cytokines in mediating pro-asthmatic-like changes in airway smooth muscle (ASM) responsiveness after inoculation of naive ASM with human RV. Isolated rabbit ASM tissues and cultured human ASM cells were exposed to RV (serotype 16) for 24 h in the absence and presence of monoclonal blocking antibodies (MAbs) or antagonists directed against either the Th2-type cytokines interleukin (IL)-4 and IL-5, intercellular adhesion molecule (ICAM)-1 (the endogenous host receptor for most RVs), or the pleiotropic proinflammatory cytokine IL-1beta. Relative to control (vehicle-treated) tissues, RV-exposed ASM exhibited significantly enhanced isometric contractility to acetylcholine and impaired relaxation to isoproterenol. These pro-asthmatic-like changes in ASM responsiveness were ablated by pretreating the RV-exposed tissues with either IL-5-receptor-alpha blocking antibody or human recombinant IL-1-receptor antagonist, whereas IL-4 neutralizing antibody had no effect. Extended studies further demonstrated that inoculation of ASM cells with RV elicited 1) an increased mRNA expression and release of IL-5 protein, which was inhibited in the presence of anti-ICAM-1 MAb, and 2) an enhanced release of IL-1beta protein, which was inhibited in the presence of IL-5 receptor-alpha antibody. Collectively, these observations provide new evidence demonstrating that RV-induced changes in ASM responsiveness are largely attributed to ICAM-1-dependent activation of a cooperative autocrine signaling mechanism involving upregulated IL-5-mediated release of IL-1beta by the RV-exposed ASM itself.

Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

“…Other studies have shown that cytokine exposure (4,5) and rhinovirus infection (6) give this same physiologic phenotype, which is accompanied by a several-fold increase in ASM G αi expression. It remains unclear how the 2 proasthmatic phenotypes of hyperresponsiveness to bronchoconstriction and resistance to bronchodilatation, which are mediated by G q - and G s -coupled receptors, respectively, could be influenced by the cellular expression levels of G i .…”

“…Figure 1 shows that tracheal expression of G αi2 assessed by Western blot increased approximately 8-fold upon IL-13 induction in these transgenic mice. These data pointed toward increased G i as a common feature of asthmatic-like airways from passive sensitization with asthmatic serum (3), cytokines (4,5), and rhinovirus exposure (6) as well as increased IL-13 production. However, these prior studies do not indicate whether isolated changes in G i levels influence airway contraction or relaxation responses, nor do they implicate the increase in G i in these models as a mechanism that underlies altered airway signaling or address whether the increase represents a compensatory event.…”

Role of Interleukin-1 and MyD88-Dependent Signaling in Rhinovirus Infection

“…One potential mechanism of the amplification of responses in our coinfection model is IL-1␤-induced upregulation of the receptors responsible for viral infection or detection. Indeed, major-group RVs cause the endogenous release of IL-1␤, which then acts in an autocrine manner to further potentiate inflammatory responses, for example, through upregulation of the RV major group receptor ICAM-1 (18,19,58). However, we found that while IL-1␤ enhanced CXCL8 release from virally infected epithelial cells, it did not augment virally induced ISGs, having no impact on CXCL10 production and in fact modestly reducing CCL5 release, implying that the cooperation of stimuli exerts selective actions on specific pathways.…”

Effect of clarithromycin on rhinovirus-16 infection in A549 cells

“…RV infection also induces the hypersecretion of mucus [7], as well as the increased expression and secretion of various cytokines, including interleukin (IL)-1b, IL-6, IL-8, IL-9, IL-11, and tumour necrosis factor-a [6][7][8]. The actions of these cytokines, either individually or in combination, are likely to underlie the clinical manifestation of RV infection [9].…”