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Study of STAT and SOCS proteins expression in chronic obstructive pulmonary disease development: comparison between the local and systemic immune responses

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Author(s):
Juliana Dias Lourenço
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
Defense date:
Examining board members:
Fernanda Degobbi Tenorio Quirino dos Santos Lopes; Alessandra Choqueta de Toledo Arruda; Milton de Arruda Martins; Iolanda de Fátima Lopes Calvo Tibério
Advisor: Fernanda Degobbi Tenorio Quirino dos Santos Lopes
Abstract

Introduction: The differentiation of TCD4+ cells into the different subtypes is mediated by the signalling of Signal Transducers and Activators of Transcription (STAT) and the Suppressor of Cytokine Signalling (SOCS) proteins. In Chronic Obstructive Pulmonary Disease (COPD), the T helper (Th) 1, Th17 and regulatory T (Tregs) subtypes are involved. However, the imbalance between the pro and anti-inflammatory responses mediated by Th17 and Treg cells is described as a fundamental mechanism in the disease development and progression. Thus, the aim of this study was to evaluate the expression of STAT and SOCS proteins involved in TCD4+ cells differentiation, especially the Th17 and Treg subtypes, in COPD development, comparing both local and systemic responses. Methods: Samples of lung tissue and peripheral blood were collected from 24 patients who underwent pulmonary resection and divided into two groups: Non-Obstructive Smokers (NOS) and COPD stages I and II. For the evaluations carried out in the peripheral blood, a third group comprising 14 patients with COPD stages III and IV was included. Gene expression of SOCS1 and 3, STAT1, 3 and 5, Retinoic-acid-related orphan receptor (RORyT), Forkhead box p3 (Foxp3), T-box-expressed-in-T-cells (T-bet), Interleukins (IL)-6, 17, 10 and Transforming Growth Factor (TGF)-beta, was evaluated in lung tissue samples and total blood leukocytes using the real-time PCR technique. The expression of total and phosphorylated proteins SOCS1 and 3, STAT1, 3 and 5 was evaluated by Western Blotting in the same compartments. Additionally, the levels of IL-6, 10, 17, 12, Interferon-gamma (IFN-y) and TGF-beta in lung tissue and blood plasma were evaluated by ELISA. Results and Discussion: The tissue lung sample analyses revealed an increase in gene expression of STAT1 and 3, RORyt, Foxp3, IL-6, TGF-beta and an increase in IL-6 levels, in addition to decreased expression of pSTAT5 protein and the pSTAT5/STAT5 ratio in patients with COPD I and II. Whereas in systemic response, was observed an increase in gene expression of STAT1 and 3 in COPD III and IV group compared to the others, and an increase in T-bet, RORyt, IL-6, TGF-beta and expression of the total STAT3 protein in COPD III and IV group compared to the COPD I and II. Increased levels of IL-6 in blood plasma were observed in COPD I and II group compared to the NOS group. Moreover, an increase in STAT5 gene expression was demonstrated in COPD III and IV group, although there was a decrease in Foxp3 expression in COPD I and II group, accompanied by a decrease in IL-10 levels in COPD III and IV group compared to individuals with COPD I and II. In addition, the analysis of SOCS protein expression demonstrated only an increase in SOCS3 gene expression in lung tissue from patients with COPD I and II, and leukocytes from patients with COPD III and IV compared to the others. Conclusions: We observed differentiation for the Th17 response in lung tissue samples since initial stages of COPD, whereas in systemic response these changes occur in more severe stages. However, the intracellular signalling for Treg response seems to vary depending on the compartment analysed, with a decrease in IL-10 levels in advanced stages of disease, reinforcing the idea that there is a failure in Treg activity in the development and progression of COPD (AU)

FAPESP's process: 16/21408-6 - THE ROLE OF SOCS AND STATS PROTEINS ON THE DIFFERENTIATION OF TCD4+ NAIVE CELLS IN THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) DEVELOPMENT: COMPARATIVE ANLYSIS BETWEEN LOCAL AND SYSTEMIC IMMUNOLOGICAL RESPONSE
Grantee:Juliana Dias Lourenço
Support Opportunities: Scholarships in Brazil - Doctorate