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Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation. [ABSTRACT FROM AUTHOR]

Objective: A central role for eosinophils in the pathogenesis of asthma was recently nullified when it was shown that treatment with anti- IL-5 monoclonal antibody (mAb), mepolizumab, did not affect post-allergen airway hyperresponsiveness (AHR) in mild asthmatics. We hypothesized that the reason was airway remodeling. Design: We evaluated the effects of anti-IL-5 and anti-IL-5 receptor alpha (IL-5Rα) mAbs in murine asthma models with and without remodeling. Materials and Methods: BALB/c mice were immunized with ovalbumin adsorbed to alum at days 0 and 5. The mice without remodeling received inhaled ovalbumin at day 17, while the mice with remodeling received inhaled ovalbumin daily from days 17 to 30. Then, anti-IL-5 mAb or anti-IL-5Rα mAb was given 24 hours before challenge, and AHR were measured 24 hours after challenge. Also, IL-5R„ expression in human airway smooth muscle cells (ASMCs) was measured by immunocytochemistry. The effect of IL-5 on human ASMCs growth and its inhibition by the mAb were determined. Results: Both anti-IL-5 mAb and anti-IL-5Rα mAb inhibited airway eosinophilia and AHR in the mice without remodeling. In the remodeling model, anti-IL-5 mAb suppressed airway eosinophilia but not AHR. However, anti-IL-5Rα mAb inhibited both airway eosinophilia and AHR. Expression of IL-5Rα and growth were stimulated by IL-5 in human ASMCs; and the growth was inhibited by pretreatment with anti-IL-5Rα mAb, but not anti-IL-5 mAb. Conclusion: These results suggest that AHR is caused by IL-5 signaling via expression of 1L-5Rα in human ASMCs, and airway remodeling is more important than inflammation. Monoclonal antibody against IL-5Rα, but not IL-5, can inhibit AHR in asthma with remodeling. [ABSTRACT FROM AUTHOR]