Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein

Pulmonary Clara cell secretory 10-kd protein (CC10) is a steroid-inducible and potentially anti-inflammatory cytokine, but its direct involvement in the regulation of T-cell responses remains unknown. The role of CC10 in the regulation of T(H)2 cytokine expression was investigated. The levels of cyt...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2004-09, Vol.114 (3), p.664-670
Main Authors: HUNG, Chih-Hsing, CHEN, Li-Chen, ZHONGJIAN ZHANG, CHOWDHURY, Bhabadeb, LEE, Wan-Ling, PLUNKETT, Beverly, CHEN, Chien-Ho, MYERS, Allen C, HUANG, Shau-Ku
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell culture
Cytokines
Cytokines - genetics
Cytokines - metabolism
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Gene expression
Gene Expression Regulation
Immunopathology
Lung - immunology
Lung - metabolism
Lymphocyte Activation
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteins
Recombinant Proteins - immunology
Rodents
Spleen - cytology
Spleen - immunology
Studies
Th2 Cells - immunology
Uteroglobin - genetics
Uteroglobin - metabolism
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Summary:Pulmonary Clara cell secretory 10-kd protein (CC10) is a steroid-inducible and potentially anti-inflammatory cytokine, but its direct involvement in the regulation of T-cell responses remains unknown. The role of CC10 in the regulation of T(H)2 cytokine expression was investigated. The levels of cytokine and GATA-3 expression were determined by ELISA and RT-PCR, respectively. Bronchoalveolar lavage fluid cell counts were also determined by using a standard protocol. CC10 expression in vivo was determined by immunocytochemistry and Western blotting. In vitro, a significant, dose-dependent suppressive effect of CC10 was found on T(H)2 cytokine expression, but not IFN-gamma, in splenocytes of antigen-sensitized mice. A similar suppressive effect was also noted in polarized CD4(+) T(H)2 cells, but not in naive CD4(+) T cells. In contrast, CC10 was able to induce IFN-gamma expression in naive CD4(+) T cells, but not in polarized T(H)1 cells. Furthermore, the suppression of T(H)2 cytokine expression was concomitant with reduction of a critical transcription factor, GATA-3. Of significance was the finding that although no significant change was found in the decay kinetics of T(H)2 cytokine transcripts, a significant decrease in mRNA stability of GATA-3 was seen in CC10-treated cells. In vivo, reconstitution of the CC10 gene in CC10-deficient mice resulted in significantly lower levels of T(H)2 cytokines, concomitant with a decrease in GATA-3 expression, after challenge with Ag compared with those seen in mock-transduced mice, which are associated with reduced levels of pulmonary eosinophilia. These results demonstrate, that CC10 plays a direct role in the regulation of T-cell-mediated inflammatory responses.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2004.05.042