Rhinovirus Activates Interleukin-8 Expression via a Src/p110β Phosphatidylinositol 3-Kinase/Akt Pathway in Human Airway Epithelial Cells

Abstract

Rhinovirus (RV) is a single-stranded RNA virus from the Picornaviridae family responsible for the majority of common colds. Viral infections trigger the majority of asthma exacerbations (17, 22), and RV accounts for 60% of virus-induced exacerbations (17). RV is also an important trigger of chronic obstructive pulmonary disease exacerbations (28,32).Numerous studies suggest a role for interleukin-8 (IL-8) in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) exacerbations. IL-8, a CXC chemokine with the neutrophil attractant Glu-Leu-Arg (ELR) motif, and neutrophils are found in the nasal secretions and sputa of patients with RV-induced asthma exacerbations (8,9,12,13,26). Further, the number of neutrophils correlates with the level of IL-8 (9, 26). RV induces IL-8 expression in cultured airway epithelial cells (34,38,39). Increased neutrophil and IL-8 levels are a feature of asthma (23, 24) and COPD exacerbations (1, 10, 27). Together, these data suggest that RV may stimulate asthma and COPD exacerbations by inducing bronchial epithelial cell production of IL-8, leading to a neutrophilic inflammatory response.We have recently shown that infection of human bronchial epithelial cells with RV serotype 39 (RV39) induces rapid phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3 (PI 3)-kinase, as well as that of Akt, a downstream effector of PI 3-kinase (21). RV39 also colocalized with CitAkt-PH, a fluorescent fusion protein containing the pleckstrin homology domain of Akt, indicating that PI(3,4,5)P 3 accumulates at the site of RV infection. Finally, inhibitions of PI 3-kinase activation with a chemical inhibitor and with dominant-negative p85␣ each inhibited RV39-induced IL-8 expression. However, the precise mechanism by which RV activates PI 3-kinase and the specific class IA PI 3-kinase catalytic subunit involved in RV-induced Akt phosphorylation were not determined.Potential upstream activators of PI 3-kinase include the tyrosine kinase p60 Src and focal adhesion kinase, each of which regulates the remodeling of the actin cytoskeleton in response to cell adhesion and integrin clustering. Upon stimulation, Src translocates from the perinuclear region of the cell to peripheral sites of integrin clustering. Src binds to its substrates via its Src homology domains, which in turn interact with phosphotyrosine-containing or proline-rich sequences. Among its substrates are Src itself (autophosphorylation at tyrosine-416), focal adhesion kinase, and the p85 regulatory subunit of PI 3-kinase (15). p85 PI 3-kinase, in turn, may form heterodimers with one of three class IA PI 3-kinase catalytic subunits (p110␣, p110␤, and p110␦). p110␣ and p110␤ are ubiquitously expressed, whereas p110␦ expression is largely restricted to cells of the immune system (4).The human RVs include more than 100 serotypes, which are

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

“…Previous studies have shown that RV-39 (a major group virus)-induced IL-8 expression in epithelial cells occurred by ICAM binding and activation of PI3K (17,22). In our studies, we also found that inhibition of PI3K down-regulated both IL-8 and IL-6 mRNA induced by RV1b.…”

Syk Associates with Clathrin and Mediates Phosphatidylinositol 3-Kinase Activation during Human Rhinovirus Internalization

“…Similar observations have been made in dendritic cells where Syk deficiency in dendritic cells derived from Syk knockout mice (29) or dendritic cells treated with pharmacological inhibitors (66) exhibited impaired Fc␥R-mediated internalization and presentation of MHC class II-restricted Ags. Syk-mediated endosomal traffic regulates other aspects of (14,44). Open arrows denote the HRV-induced signaling pathway described in the current article identifying Syk to be downstream of Src and to mediate PI3K activation and clathrin-mediated endocytosis of HRV.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…TNF-a disrupts airway epithelial barrier function and this is mediated via Src activation and prevented by a Src inhibitor SU6656 [2,3-dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide] (Hardyman et al, 2013). The Src inhibitor PP2 and siRNA knockdown of Src prevents rhinovirusinduced release of CXCL8 from human airway epithelial cells (Bentley et al, 2007). Analysis of an asthma protein interactome suggests that Src plays a central role and may be a good target to inhibit (Randhawa and Bagler, 2012).…”