Abstract
Since their discovery, Suppressors of Cytokine Signaling, or SOCS proteins, have been found in numerous cell types, but their role in asthma is not completely clear. Although the exact mechanisms are unclear and interpretations are conflicting, SOCS proteins play important role in airway homeostasis by inhibiting cytokine signaling contributing to asthma pathology. In this study, it was confirmed that expression of SOCS proteins, specifically SOCS-1, SOCS-2, SOCS-3, and SOCS-5 are upregulated in the lungs in response to the development of AHR. SOCS expression was localized via positive IHC staining to the airway epithelial cells in sections of lungs and showed they have the ability to express SOCS proteins in response to AHR. Also contributing to airway homeostasis is the newly discovered class of regulatory T lymphocytes. Therefore, after establishing that an adoptive transfer of T regulatory cells effectively reverses AHR. IHC was again used to study the expression of SOCS. Lung sections of mice receiving an adoptive transfer of Tregs showed a lack of localized expression of SOCS-1. SOCS-2, SOCS-3, and SOCS-5 in the airways epithelial cells. Using ELISA, we show levels of the pro-inflammatory cytokine IL-6 are significantly increased in the BALF of sensitized and challenged mice as compared to control mice. Subsequently, IL-6 levels in the BALF of mice having received an adoptive transfer of Tregs are consistent with control mice. To further understand of the role of epithelial cells in regulating SOCS expression, we employed the use of in vitro cell stimulation of human airway epithelial cells. Cytokines shown to play a role in asthma were used for stimulation including the pro- inflammatory JL-6, the Th2 cytokine IL-5, and the two cytokines essential for TH1/ TH2 differentiation, IL-4 and IL-12. Expression of all four SOCS of interest was induced at the mRNA level following IL-6 stimulation. Additionally, we show a reciprocal induction pattern with IL-4 inducing mRNA expression of SOCS-3 but having no effect on SOCS-5 and IL-12 having no effect on SOCS-3 and inducing mRNA expression of SOCS-5. The complete mechanisms elucidating the induction of SOCS and their inhibitory functions are unknown. Herein we demonstrate that AECs express SOCS at both the mRNA and protein levels. We propose that AECs are involved in AHR reversal and have a role in T regulatory cell immunomodulation. The data presented herein provide a link between airway epithelial cells and the expression of SOCS-1, SOCS-2, SOCS-3, and SOCS-5 in asthma.