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


OBJECTIVE
The role of CC10 in the regulation of T(H)2 cytokine expression was investigated.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results demonstrate, that CC10 plays a direct role in the regulation of T-cell-mediated inflammatory responses.
Hung
Chih-Hsing
CH
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224-6801, USA.
Chen
Li-Chen
LC
Zhang
Zhongjian
Z
Chowdhury
Bhabadeb
B
Lee
Wan-Ling
WL
Plunkett
Beverly
B
Chen
Chien-Ho
CH
Myers
Allen C
AC
Huang
Shau-Ku
SK
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D011994:Recombinant Proteins; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin