ABSTRACT
Introducción: La artritis reumatoidea se caracteriza por inflamación de la membrana sinovial debido al infiltrado de células inmunitarias que secretan citocinas relacionadas a perfil Th17 como IL-22 e IL-6. La dinámica de estas citocinas durante el tratamiento permanece incomprendida. El objetivo fue evaluar los niveles séricos y en líquido sinovial (LS) de IL-22 e IL-6, correlacionarlos con diferentes parámetros bioquímicos y clínicos y medir sus cambios post-tratamiento. Material y métodos: Se estudiaron 77 pacientes con AR y 30 controles. A 30 pacientes se los evaluó nuevamente luego de 3 meses de tratamiento y a 12 se les extrajo LS. Se midió VSG, PCR, FR, anti-CCPhs, IL-22 e IL-6. Se evaluó la actividad con DAS28 y respuesta al tratamiento con criterios EULAR. Resultados: IL-22 e IL-6 fueron similares entre pacientes y controles. Sus niveles disminuyeron luego del tratamiento, principalmente en pacientes respondedores. IL-22 fue menor e IL-6 mayor en LS que en sangre. IL-6 correlacionó positivamente con PCR y anti-CCPhs. Los niveles de VSG, PCR y DAS28 fueron mayores en pacientes con valores dosables de IL-6 que en no dosables. Conclusión: En pacientes con valores basales dosables de IL-22 e IL-6, los niveles de estas citocinas podrían utilizarse como marcador adicional de respuesta al tratamiento.
Introduction: Rheumatoid arthritis is characterized by synovium inflammation due to the infiltration of immune cells that secrete Th17 cytokines like IL-22 and IL-6. The dynamics of these cytokines during the treatment remain unknown. The aim of this study was to evaluate the levels of IL-22 and IL-6 serum and synovial fluid (SF) in correlation with different biochemical and clinical parameters and treatment-associated changes. Material and methods: Seventy-seven RA patients and 30 controls were recruited. Thirty patients were evaluated after 3 months of treatment and SF was collected of 12 patients. ESR, CRP, RF, anti-CCP hs, IL-22 e IL-6 were measured. DAS28 was used to assess disease activity and response to treatment followed EULAR criteria. Results: There were not differences in serum IL-22 and IL-6 levels between patients and controls. Cytokine levels decreased after treatment, mainly in responder patients. IL-22 was decreased and IL-6 was increased in SF compared to serum. IL-6 correlated positively with CRP and anti-CCPhs. ESR, CRP and DAS28 were increased in patients with detectable IL-6 compared to those with undetectable IL-6. Conclusion: In patients with detectable serum IL-22 and IL-6 levels before treatment initiation, follow-up of cytokine levels could be an useful additional tool to evaluate treatment response.
Subject(s)
Arthritis, Rheumatoid , Therapeutics , Interleukins , Interleukin-6 , InflammationABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Thyroid cancer is the most common endocrine malignancy. Anaplastic thyroid cancer is one of the most aggressive thyroid tumors. It is known that activation of oncogenes and/or inactivation of tumor suppressor genes in tumor cells promotes tumorigenesis. The microenvironment of the tumor also plays a key role on cancer development and progression in a variety of tumors. However, the mechanisms by which tumor-stroma crosstalk in thyroid cancer remains poorly characterized. In this study we aimed to understand how interactions between fibroblasts and anaplastic thyroid cancer cells contribute to thyroid carcinogenesis. We first characterized the phenotypic changes of human fibroblasts in vitro through co-cultures by using transwells as well as by using anaplastic thyroid cancer cells-derived conditioned media. We found that fibroblasts acquired an activated phenotype or also known as cancer-associated fibroblast phenotype after being in contact with soluble factors secreted from anaplastic thyroid cancer cells, compared to the fibroblasts in mono-cultures. All the changes were partly mediated through Src/Akt activation. Treatment with the antioxidant N-acetyl-cysteine reversed in part the metabolic phenotype of activated fibroblasts. Remarkably, conditioned media obtained from these activated fibroblasts promoted cell proliferation and invasion of follicular thyroid cancer cell line, FTC-133 cells. Thus, a reciprocal and dynamic interaction exists between tumor and stromal cells, which results in the promotion of thyroid tumorigenesis. The present studies have advanced the understanding of the molecular basis of tumor-stroma communications, enabling identification and targeting of tumor-supportive mechanisms for novel treatment modalities.
Subject(s)
Adenocarcinoma, Follicular/pathology , Cancer-Associated Fibroblasts/metabolism , Stromal Cells/pathology , Thyroid Carcinoma, Anaplastic/pathology , Thyroid Neoplasms/pathology , Carcinogenesis/pathology , Cell Communication , Cell Culture Techniques , Cell Dedifferentiation , Cell Line, Tumor , Cell Proliferation , Coculture Techniques , Culture Media, Conditioned/metabolism , Disease Progression , Humans , Neoplasm Invasiveness/pathology , Paracrine Communication , Thyroid Gland/cytology , Thyroid Gland/pathology , Tumor MicroenvironmentABSTRACT
BACKGROUND/AIMS: Although a cross-talk between immune and endocrine systems has been well established, the precise pathways by which these signals co-regulate pro- and antiinflammatory responses on antigen-presenting cells remain poorly understood. In this work we investigated the mechanisms by which triiodothyronine (T3) controls T cell activity via dendritic cell (DC) modulation. METHODS: DCs from wild-type (WT) and IL-6-deficient mice were pulsed with T3. Cytokine production and programmed death protein ligands (PD-L) 1 and 2 expression were assayed by flow cytometry and ELISA. Interferon-regulatory factor-4 (IRF4) expression was evaluated by RT-qPCR and flow cytometry. The ability of DCs to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the different profile markers were analyzed by flow cytometry and ELISA. For in vivo experiments, DCs treated with ovalbumin and T3 were injected into OTII mice. Proliferation, cytokine production, frequency of FoxP3+ regulatory T (Treg) cells and PD-1+ cells were determined by MTT assay, ELISA and flow cytometry, respectively. RESULTS: T3 endows DCs with pro-inflammatory potential capable of generating IL-17-dominant responses and down-modulating expression of PD-L1 and 2. T3-stimulated WT-DCs increased the proportion of IL-17-producing splenocytes, an effect which was eliminated when splenocytes were incubated with T3-treated DCs derived from IL-6-deficient mice. Enhanced IL-17 expression was recorded in both, CD4- and CD4+ populations and involved the IRF-4 pathway. Particularly, γδ-T cells but not natural killer (NK), NKT, B lymphocytes nor CD8+ T cells were the major source of IL-17-production from CD4- cells. Moreover, T3-conditioned DCs promoted a decrease of the FoxP3+ Treg population. Furthermore, T3 down-modulated PD-1 expression on CD4- cells thereby limiting inhibitory signals driven by this co-inhibitory pathway. Thus, T3 acts at the DC level to drive proinflammatory responses in vitro. Accordingly, we found that T3 induces IL-17 and IFNγ-dominant antigen-specific responses in vivo. CONCLUSION: These results emphasize the relevance of T3 as an additional immune-endocrine checkpoint and a novel therapeutic target to modulate IL-17-mediated pro-inflammatory responses.
