Uteroglobin Suppresses SCCA Gene Expression Associated with Allergic Asthma

Abstract

Uteroglobin (UG), the founding member of the Secretoglobin superfamily, is a potent anti-inflammatory protein constitutively expressed at a high level in the airway epithelia of all mammals. We previously reported that the lungs of UG-knock-out (UG-KO) mice express elevated levels of Th2 cytokines (e.g. interleukin (IL)-4 and IL-13), which are augmented by allergen sensitization and challenge leading to exaggerated airway inflammation. Notably, these responses are suppressed by recombinant UG treatment (Mandal, A. K., Zhang, Z., Ray, R., Choi, M. S., Chowdhury, B., Pattabiraman, N., and Mukherjee, A. B. (2004) J. Exp. Med. 199, 1317-1330). Recent reports indicate that human orthologs of murine squamous cell carcinoma antigen-2 (SCCA-2/serpinb3a), a serine proteaseinhibitor, are overexpressed in the airways of asthmatic patients. We report here that compared with wild type littermates, UG-KO mouse lungs express markedly elevated levels of SCCA-2 mRNA and protein, which are augmented by allergen-challenge. Most importantly, these effects are abrogated by recombinant UG treatment. We further demonstrate that treatment of cultured human bronchial epithelial cells with IL-4 or IL-13 stimulates phosphorylation of STAT-1 and STAT-6 leading to SCCA-1 (SERPINB3) and SCCA-2 (SERPINB4) gene expression. We propose that: (i) IL-4-and IL-13-stimulated SCCA gene expression is mediated via STAT-1 and STAT-6 activation, and (ii) by suppressing the production, and most likely by interfering with the signaling of these cytokines, UG inhibits SCCA gene expression associated with airway inflammation in asthma. Uteroglobin (UG)1 is a steroid-inducible, homodimeric, multifunctional secreted protein with potent anti-inflammatory and immunomodulatory properties (reviewed in Ref. 1). The founding member of the secretoglobin superfamily of proteins (2), UG, is constitutively expressed at a high level in the pulmonary mucosal epithelial cells of virtually all mammals including mice. We previously reported that compared with wild type (WT) littermates, the lungs of the UG-knock-out (UG-KO) mice express markedly higher levels of Th2 cytokines and manifest exaggerated airway inflammatory response to allergens marked by elevated levels of eosinophil infiltration (3, 4). All of these are characteristically found in human airway inflammatory diseases such as bronchial asthma in which sensitivity to allergens play a critical pathogenic role.Recently, it has been reported that the expression of squamous cell carcinoma antigens (SCCA), cysteine, and chymotrypsin proteinase inhibitors of the ovalbumin/serpin family (reviewed in Ref. 5; Ref. 6) is markedly elevated in the airway epithelia of patients with bronchial asthma (7). Consistent with these findings, it has also been reported that SCCA protein targets a potent allergen and an extrinsic cysteine proteinase in house-dust mites, which is thought to play a pathogenic role in allergic asthma (8), although the physiological role(s) of SCCA is yet to be defined.In humans, SCCA-1 and SCCA-2 genes enc...

STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage

“…Among 17 SERPINs filtered in the microarray, gene expression of SPINT2, SERPINB3/squamous cell carcinoma antigen (SCCA)-1, SERPINB4/SCCA-2, and SERPINB13/Hurpin were induced significantly. SCCA-1 and 2 are expressed through STAT6 activation by IL-4 treatment (Ray et al 2005). All these induced expressions of B clade SERPINs were confirmed to be governed by STAT6 activation during T. gondii infection.…”

SERPINB3 and B4: From biochemistry to biology

“…Systemic Serpinb3a knockout mice are developmentally normal but display attenuated pro-inflammatory response in an asthma model [35]. This is in line with the elevated expression of SERPINB3/B4 in human airway inflammatory diseases [36-38]. Therefore, while the lack of overt developmental phenotype may be due to the compensatory effect of other Serpins such as Serpinb3b and Serpinb3c, it is also possible that SERPINB3/B4 mostly function as a stress-responsive factor.…”

Uteroglobin: A Steroid-Inducible Immunomodulatory Protein That Founded the Secretoglobin Superfamily

“…The authors proposed that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses. Furthermore, UG-KO mice appear to manifest a high level of expression of the SCCA gene, reported to be associated with allergic asthma (220). This may be related to the suppressive effects of UG on allergeninduced differentiation of T-helper 2 (T H 2) cells (221)(222)(223).…”