Uteroglobin suppresses SCCA gene expression associated with allergic asthma.
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 protease-inhibitor, 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.
Ray
Rabindranath
R
Section on Developmental Genetics, Heritable Disorders Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Choi
Moonsuk
M
Zhang
Zhongjian
Z
Silverman
Gary A
GA
Askew
David
D
Mukherjee
Anil B
AB
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000737:chemistry; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D015843:Serpins / Q000096:biosynthesis* / Q000737:chemistry; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics* / Q000502:physiology*
D000951:Antigens, Neoplasm; D016207:Cytokines; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015843:Serpins; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; C051072:squamous cell carcinoma-related antigen; D015847:Interleukin-4; D014598:Uteroglobin