Regulation of T_H2 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_H2 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_H2 cytokine expression, but not IFN-γ, in splenocytes of antigen-sensitized mice. A similar suppressive effect was also noted in polarized CD4⁺ T_H2 cells, but not in naive CD4⁺ T cells. In contrast, CC10 was able to induce IFN-γ expression in naive CD4⁺ T cells, but not in polarized T_H1 cells. Furthermore, the suppression of T_H2 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_H2 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_H2 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. Conclusion These results demonstrate, that CC10 plays a direct role in the regulation of T-cell-mediated inflammatory responses.