The cytokine-driven regulation of secretoglobins in normal human upper airway and their expression, particularly that of uteroglobin-related protein 1, in chronic rhinosinusitis

Abstract

BackgroundThe involvement of secretoglobins (SCGBs) other than SCGB1A1 (Clara cell 10-kDa protein, CC10) in human airway diseases remains unexplored. Among those SCGBs, SCGB3A2 (uteroglobin-related protein 1, UGRP1) is particularly interesting, given its structure and function similarities with SCGB1A1 (CC10). The aim of this study was to investigate the expression regulation of SCGBs other than SCGB1A1 (CC10) in human upper airway, and their potential involvement, particularly that of SCGB3A2 (UGRP1), in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP).MethodsEight SCGB family members including SCGB3A2 (UGRP1), SCGB1C1 (ligand binding protein RYD5), SCGB1D1 (lipophilin A), SCGB1D2 (lipophilin B), SCGB1D4 (interferon-γ inducible SCGB), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), and SCGB3A1 (uteroglobin-related protein 2) were studied. The regulation of SCGBs mRNA expression in normal nasal mucosa by proinflammatory, Th1, and Th2 cytokines was studied through nasal explant culture. SCGBs mRNA expression levels in CRSsNP and CRSwNP patients and controls were compared. The mRNA levels were detected by means of quantitative reverse transcriptase-polymerase chain reaction. The protein expression of SCGB3A2 (UGRP1) was analyzed using immunohistochemistry.ResultsThe expression of SCGBs except SCGB1D2 (lipophilin B) could be found in upper airway and be differentially regulated by different cytokines. SCGB3A2 (UGRP1) mRNA expression was induced by Th1 cytokine, but suppressed by proinflammatory and Th2 cytokines. SCGBs mRNA expression was altered in CRS; particularly, SCGB3A2 (UGRP1) protein and mRNA expression was markedly decreased in both CRSsNP and CRSwNP and its protein levels inversely correlated with the number of total infiltrating cells, preoperative sinonasal CT scores, and postoperative endoscopy and symptom scores.ConclusionSCGBs except SCGB1D2 (lipophilin B) are expressed in human upper airway and their expression can be differentially regulated by inflammatory cytokines. SCGBs mRNA expression is altered in CRS. Reduced production of UGRP1, which is likely due, at least in part, to a local cytokine environment, may contribute to the hyper-inflammation in CRS and correlates with response to surgery.

Update of the human secretoglobin (SCGB) gene superfamily and an example of 'evolutionary bloom' of androgen-binding protein genes within the mouse Scgb gene superfamily

“…For example, mRNA expression of every SCGB family member (except SCGB1D2) has been demonstrated in human airways. 4 In general, the physiological and pathophysiological functions of most individual SCGBs remain to be defined. Nevertheless, roles currently ascribed to SCGBs include lung maintenance and repair, immune modulation and, at least in rodents, mate selection.…”

Single-Nucleotide Polymorphisms on theRYD5Gene in Nasal Polyposis

“…It has been known that the cytokine-driven regulation of expression in the SCGB superfamily in the airways plays a role in the pathogenesis of some diseases, such as asthma, rhinitis, and NP (Dear et al, 1991;Mukherjee et al, 1999;Jackson et al, 2011;Lu et al, 2011;Pala et al, 2014). Similar to other secretory proteins, RYD5 protein is a member of the SCGB superfamily and it has a hydrophobic N-terminal region with a 14 amino acid signal peptide sequence, which is required for its channeling into the target organelle (Dear et al, 1991;Lu et al, 2011). As it leads to the signal peptide domain, it probably affects the function of the signal peptide motifs of RYD5 protein that is expressed in nasal mucosa (Arg5Cys) (Dear et al, 1991).…”

“…As it leads to the signal peptide domain, it probably affects the function of the signal peptide motifs of RYD5 protein that is expressed in nasal mucosa (Arg5Cys) (Dear et al, 1991). In addition, it was shown that IFN-gamma downregulated and TH2 cytokines, namely IL-4 and IL-13, upregulated mRNA expression of RYD5 in patients with CRS with NP, but not in CRS patients without NP (Lu et al, 2011). Therefore, it may be postulated that that RYD5 may be a modifying factor for NP.…”

“…In a study conducted on CRS patients with or without NP, increased RYD5 expression was only observed in CRS patients with NP. The authors concluded that increased expression of RYD5 might contribute to the polyp formation (Lu et al, 2011). Those findings indicated that RYD5 could play a role in NP formation.…”

“…They have been indicated as candidates for a new cytokine family owing to their anti-inflammatory and immunomodulatory functions. The SCGB superfamily has been rapidly expanding with the discovery of many new human genes (Mukherjee et al, 1999;Jackson et al, 2011;Lu et al, 2011). Some SCGBs have been associated with a number of disease states involving airways, including asthma, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease, either as contributing agents or biomarkers (Reynolds et al, 2002).…”