Corticosteroid and Cytokines Synergistically Enhance Toll-Like Receptor 2 Expression in Respiratory Epithelial Cells

Abstract

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and beta-defensin-2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.

Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells

“…In the same way, responsiveness to the Grampositive bacterium S. aureus could be induced by transfection of TLR2 and TLR2/CD36, thus paralleling the findings with LTA. Moreover, it has been reported that TNF-␣ and IFN-␥ increase expression of TLR2 in respiratory epithelial cells (30). Indeed, we observed that prestimulation of BEAS-2B cells with a combination of these both cytokines increased TLR2 mRNA expression (Fig.…”

Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

“…In fact, genetic complementation experiments with human TLR7 and TLR8 suggest that TLR8, not TLR7, is responsible for the recognition of single-stranded RNA in humans (41). Moreover, TLR7 and TLR8 are not expressed in human bronchial epithelial cells (44), and our experiments using a vector encoding a dominant-negative form of MyD88 rule out a role for those receptors in the activation of influenza A-infected human epithelial cells. Indeed, it was established that MyD88 is essential for the signaling downstream from TLR7 and TLR8 (41)(42)(43)45).…”

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

“…In contrast, the activation of IRF-3 induces production of type I IFN and induces an anti-viral response. Airway epithelial cells have been shown to express mainly TLR2-6 [4,5]. TLR2, which is heterodimerized with TLR1 or TLR6, recognizes bacterial components such as lipoprotein, peptidoglycan (PGN) and lipoteichoic acid, GPI anchor from protozoa and some viral envelope proteins such as those expressed by measles virus and human cytomegalovirus.…”

“…Expression of the type I IFN, IFN-β, and type III IFNs, IFN-λ1 (IL-29) and IFN-λ2/3 (IL-28A/B), is important in the antiviral response of the epithelium. TLR3 and RNA helicases are important sensors for detection of viral infection and induce production of IFN-β and IFN-λ in epithelial cells [4][5][6][7]. Type II IFN, IFN-γ, which is produced from activated T cells and NK cells, also activates IFN-λ production in epithelial cells, probably amplifying the antiviral effects of specific T cells.…”