The cellular protein retinoic acid-inducible gene I (RIG-I) senses intracellular viral infection and triggers a signal for innate antiviral responses including the production of type I IFN. RIG-I contains a domain that belongs to a DExD/H-box helicase family and exhibits an N-terminal caspase recruitment domain (CARD) homology. There are three genes encoding RIG-I-related proteins in human and mouse genomes. Melanoma differentiation associated gene 5 (MDA5), which consists of CARD and a helicase domain, functions as a positive regulator, similarly to RIG-I. Both proteins sense viral RNA with a helicase domain and transmit a signal downstream by CARD; thus, these proteins share overlapping functions. Another protein, LGP2, lacks the CARD homology and functions as a negative regulator by interfering with the recognition of viral RNA by RIG-I and MDA5. The nonstructural protein 3/4A protein of hepatitis C virus blocks the signaling by RIG-I and MDA5; however, the V protein of the Sendai virus selectively abrogates the MDA5 function. These results highlight ingenious mechanisms for initiating antiviral innate immune responses and the action of virus-encoded inhibitors.

Thymic stromal lymphopoietin (TSLP) is elevated in asthma and triggers dendritic cell-mediated activation of Th2 inflammatory responses. Although TSLP has been shown to be produced mainly by airway epithelial cells, the regulation of epithelial TSLP expression has not been extensively studied. We investigated the expression of TSLP in cytokine- or TLR ligand-treated normal human bronchial epithelial cells (NHBE). The mRNA for TSLP was significantly up-regulated by stimulation with IL-4 (5.5-fold) and IL-13 (5.3-fold), weakly up-regulated by TNF-α, TGF-β, and IFN-β, and not affected by IFN-γ in NHBE. TSLP mRNA was only significantly up-regulated by the TLR3 ligand (dsRNA) among the TLR ligands tested (66.8-fold). TSLP was also induced by in vitro infection with rhinovirus. TSLP protein was detected after stimulation with dsRNA (120 ± 23 pg/ml). The combination of TNF-α and IL-4 produced detectable levels of TSLP protein (40 ± 13 pg/ml). In addition, TSLP was synergistically enhanced by a combination of IL-4 and dsRNA (mRNA; 207-fold, protein; 325 ± 75 pg/ml). The induction of TSLP by dsRNA was dependent upon NF-κB and IFN regulatory factor 3 (IRF-3) signaling via TLR3 as indicated by a study with small interfering RNA. The potent topical glucocorticoid fluticasone propionate significantly suppressed dsRNA-dependent TSLP production in NHBE. These results suggest that the expression of TSLP is induced in airway epithelial cells by stimulation with the TLR3 ligand and Th2 cytokines and that this response is suppressed by glucocorticoid treatment. This implies that respiratory viral infection and the recruitment of Th2 cytokine producing cells may amplify Th2 inflammation via the induction of TSLP in the asthmatic airway.

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Background Chronic rhinosinusitis (CRS) has been defined as persistent symptomatic inflammation of the nasal and sinus mucosa resulting from the interaction of multiple host and environmental factors. Recent studies have implicated Alternaria fungi or toxigenic Staphylococcus aureus as critical agents in CRS pathogenesis. The emphasis on environmental agents in CRS etiology has focused interest toward elimination of those agents as the prime mechanism of therapy. This viewpoint is in marked contrast to the current perspective on some other chronic inflammatory epithelial disorders that afflict the skin, lungs, and gut, wherein host factors are believed to predispose to disease expression in the presence of ubiquitous environmental agents. Methods The current review evaluates CRS etiology from this perspective and considers that CRS develops, in part, as an outcome of a dysfunctional host response. Specifically, evidence from our laboratory and others will be reviewed indicating that CRS is associated with a failure of the mechanical and immunologic barriers across the nasal mucosa. The hypothesis would further propose that genetic and epigenetic variation predisposes susceptible individuals to barrier failure in the presence of environmental stress leading to CRS. Results From this unifying perspective, bacteria and fungi are seen as disease modifiers rather than primary etiologic agents. Conclusion The goal is to place concepts of CRS pathophysiology in a framework consistent with a current understanding of chronic inflammation in general and epithelial disease in particular.