Abstract
Th17/Treg imbalance contributes to chronic obstructive pulmonary disease (COPD) development and progression. However, intracellular signaling by suppressor of cytokine signaling (SOCS) 1 and SOCS3 and the proteins signal transducer and activator of transcription (STAT) 3 and STAT5 that orchestrate these imbalances are currently poorly understood. Thus, these proteins were investigated in C57BL/6 mice after exposure to cigarette smoke (CS) for 3 and 6 months. The expression of interleukin was measured by ELISA and the density of positive cells in peribronchovascular areas was quantified by immunohistochemistry. We showed that exposure to CS in the 3rd month first induced decreases in the numbers of STAT5+ and pSTAT5+ cells and the expression levels of TGF-β and IL-10. The increases in the numbers of STAT3+ and pSTAT3+ cells and IL-17 expression occurred later (6th month). These findings corroborate the increases in the number of SOCS1+ cells in both the 3rd and 6th months, with concomitant decreases in SOCS3+ cells at the same time points. Our results demonstrated that beginning with the initiation of COPD development, there was a downregulation of the anti-inflammatory response mediated by SOCS and STAT proteins. These results highlight the importance of intracellular signaling in Th17/Treg imbalance and the identification of possible targets for future therapeutic approaches.
Highlights
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways with parenchymal destruction, that is mainly caused by cigarette smoke (CS) exposure and characterized by persistent airflow o bstruction[1]
SOCS1 is defined as an important protein that negatively regulates the interferon-γ–STAT1 pathway[14], which is essential for Th1 cell differentiation, and SOCS3 is a specific inhibitor of S TAT315
Our results showed that decreases in intracellular signaling for Treg cell differentiation and IL-10 release in peribronchovascular areas of the lung occur prior to the modulation Th17 signaling in a CS-induced model of chronic obstructive pulmonary disease (COPD)
Summary
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways (obstructive bronchiolitis) with parenchymal destruction (emphysema), that is mainly caused by cigarette smoke (CS) exposure and characterized by persistent airflow o bstruction[1]. T cell-mediated adaptive immunity is deeply involved in the regulation of airway inflammation during COPD development[3,4], and Th17 cells, a subset of activated CD4 + T cells, are associated with the progression and exacerbation of alveolar destruction via interleukin (IL)-17 release[3,4,5,6,7]. The differentiation of T cell subsets depends on the microenvironmental stimuli produced by the release of cytokines, which in turn is mediated by intracellular proteins, including signal transducer and activator of transcription (STAT) and suppressor of cytokine signaling (SOCS) p roteins[10]. Th17 cell differentiation occurs in the presence of STAT3, which is activated by the Th17-induced cytokines IL-6, IL-23, and IL-21 and can induce RORγt gene expression. SOCS1 is defined as an important protein that negatively regulates the interferon-γ–STAT1 pathway[14], which is essential for Th1 cell differentiation, and SOCS3 is a specific inhibitor of S TAT315
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