Calpeptin may reverse glucocorticoid-resistance of allergic rhinitis associated with cigarette smoke exposure by down-regulating interferon regulatory factor 1

Abstract

Cigarette smoke exposure is an important factor in chronic inflammation in patients with allergic rhinitis (AR); however, the relationship between cigarette smoke and AR-related glucocorticoid resistance requires further study. In mice, calpeptin significantly reduces inflammation of the lower respiratory tract caused by cigarette smoke, but whether it can treat glucocorticoid-resistant AR caused by cigarette smoke requires further research. In this study, we confirmed that cigarette smoke exposure can aggravate the Th2 inflammatory response in AR leading to glucocorticoid resistance. The underlying mechanism may be related to decreased expression of DNA methyltransferase 3a (Dnmt3a), and increased expression of interferon regulatory factor 1 (IRF1). In addition, we found that calpeptin can inhibit the expression of IRF1 and thus treat AR-associated glucocorticoid resistance in rats exposed to cigarette smoke. These data suggest that calpeptin may downregulate IRF1 and therefore treat glucocorticoid resistance in AR-associated with cigarette smoke exposure.

Keywords: Allergic rhinitis; Calpeptin; Cigarette smoke; Glucocorticoid resistance; Rats; Regulatory factor 1.

Fig. 1

A: Hematoxylin-eosin (HE) staining of the nasal mucosa in each group. The eosinophil is indicated by the red arrow. B: Statistical analysis of the eosinophil count in nasal mucosa. C–D: Statistical analysis of the expression levels of IL-4 and IL-5 in the serum of patients in each group. *P < 0.05, **P < 0.01. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

A: Differential gene clustering. B: Statistics of differential genes among the three groups. C: Differential gene Wayne diagram. D: GO enrichment analysis histogram. BP, biological process; CC, cellular component; MF, molecular function. E: GO enrichment analysis scatter plot. F: KEGG enrichment analysis histogram. G: KEGG enrichment analysis scatter plot. H: Protein interaction network. a, control group; b, allergic rhinitis (AR) group; c, Smoke + AR group.

Fig. 3

A: Flow chart of animal models. B: Hematoxylin-eosin (HE) staining of the nasal mucosa of rats in each group. Eosinophils are indicated by the red arrow. C: Statistical analysis of the eosinophil count in nasal mucosa. D–G: Statistical analysis of the expression levels of IgE, IL-4, IL-5 and IL-13 in the serum of rats in each group. H–I: Statistical analysis of the percentage of Th2 cells and ILC2 cells in lymphocytes in the spleen of rats in each group. *P < 0.05, **P < 0.01. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

A: Expression of GR-α, GR-β, P38MAPK, Dnmt3a, and IRF1 proteins in the nasal mucosa of rats in each group. B: Statistical analysis of protein expression of GR-α, GR-β, P38MAPK, Dnmt3a, and IRF1. *P < 0.05, **P < 0.01.

Fig. 5

A: Hematoxylin-eosin (HE) staining of the nasal mucosa of rats in each group. Eosinophils are indicated by the red arrow. B: Statistical analysis of the eosinophil count in nasal mucosa. C–F: Statistical analysis of the expression levels of IgE, IL-4, IL-5 and IL-13 in the serum of rats in each group. G–H: Statistical analysis of the percentage of Th2 cells and ILC2 cells in the spleen of rats in each group. I: Expression of Dnmt3a and IRF1 proteins in rat nasal mucosa of each group. J–K: Statistical analysis of Dnmt3a and IRF1 protein expression. *P < 0.05, **P < 0.01. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 6

A: Expression of Dnmt3a and IRF1 proteins in RPMI-2650 cells of each group. B: Expression of IL-8 in the supernatant of RPMI-2650 cells. C–D: Statistical analysis of Dnmt3a and IRF1 protein expression. *P < 0.05, **P < 0.01.