Th17/Treg imbalance in COPD development: suppressors of cytokine signaling and signal transducers and activators of transcription proteins

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.

STAT1 regulates interferon-γ-induced angiotensinogen and MCP-1 expression in a bidirectional manner in primary cultured mesangial cells

Objective: Intrarenal interferon-γ significantly contributes to the development of glomerular injury in which angiotensinogen and monocyte chemoattractant protein 1 levels are elevated. However, the exact nature of the role that interferon-γ plays in regulating angiotensinogen and monocyte chemoattractant protein 1 expression has not been fully delineated. Therefore, the aim of this study was to investigate the role that interferon-γ plays in angiotensinogen and monocyte chemoattractant protein 1 expression. Methods: Primary cultured rat mesangial cells were treated with 0–20 ng/mL interferon-γ for 2, 8 or 24 hours. Expression levels of angiotensinogen, monocyte chemoattractant protein 1, suppressors of cytokine signaling 1, an intracellular suppressor of Janus kinase-signal transducers and activators of transcription signaling and activity of the Janus kinase-signal transducers and activators of transcription pathway were evaluated by reverse transcriptase polymerase chain reaction and western blot analysis. Results: Interferon-γ increased angiotensinogen expression in mesangial cells with maximal augmentation observed following 5 ng/mL interferon-γ at 8 hours of treatment (1.87 ± 0.05, mRNA, relative ratio). Further increases were reduced or absent using higher concentrations of interferon-γ. Following treatments, monocyte chemoattractant protein 1 expression was induced in a linear dose-dependent manner (6.85 ± 0.62-fold by 20 ng/mL interferon-γ at 24 hours). In addition, interferon-γ induced STAT1 phosphorylation and suppressors of cytokine signaling 1 expression in a linear dose-dependent manner. The suppression of STAT1 and suppressors of cytokine signaling 1 expression by small interference RNAs facilitated an increase in interferon-γ-induced angiotensinogen expression, indicating that these two factors negatively regulate angiotensinogen expression. In contrast, the increase in interferon-γ-induced monocyte chemoattractant protein 1 expression was attenuated in STAT1-deficient mesangial cells, suggesting that STAT1 positively regulates monocyte chemoattractant protein 1 expression in mesangial cells. Conclusion: These results demonstrate that while interferon-γ increases both angiotensinogen and monocyte chemoattractant protein 1 expression, STAT1 plays an opposing role in the regulation of each factor in mesangial cells.

microRNA-221 (Mir-221) Influences Ovarian Cancer Cell Proliferation and Apoptosis Through Regulating Suppressors of Cytokine Signaling 3-Janus Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) Pathway

Suppressors of cytokine signaling 3 (SOCS3) regulates JAK-STAT signaling. Bioinformatics analysis showed a targeted relationship of Mir-221 with SOCS3 mRNA. Our study assessed whether Mir221 regulates SOCS3 expression and affects ovarian cancer cells. Ovarian cancer tissues were collected and compared with adjacent tissues to detect Mir-221 and SOCS3 expression. Ovarian cancer cell line SKOV3 cells were separated into miR-NC group and Mir-221 inhibitor group followed by analysis of Mir-221, SOCS3, p-JAK2, and p-STAT3 expression, cell apoptosis and proliferation. Compared with adjacent tissues, Mir-221 expression in tumor tissues was significantly elevated and SCOS3 mRNA level was decreased. There is a targeted relationship between miR-203 and SOCS3 mRNA. Compared with IOSE80 cells, ovarian cancer A2780 and SKOV3 cells presented significantly elevated Mir-221 level and decreased SOCS3 expression. Mir-221 inhibitor transfection significantly upregulated SOCS3, downregulated p-JAK2, p-STAT3 protein, promoted cell apoptosis and inhibited proliferation. The increased Mir-221 and decreased SOCS3 expression are related to the pathogenesis of ovarian cancer. Mir-221 downregulates SOCS3, affects the activity of JAK-STAT signaling, and regulates ovarian cancer cell proliferation and apoptosis.