Pharmacological reports : PR · 2025
Thiazolidine derivative (LPSF/CR-35) modulates the production of IL-17A, IL-10, IL-4, TFN, CCL2 and CXCL8 in PBMC from systemic sclerosis patients.
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Tavares Dantas Andréa, Rodrigues de Almeida Anderson, Ferraz Cordeiro Marina, Santana de Oliveira Priscilla Stela, da Silva Moura José Arion, Pereira Michelly Cristiny, Barreto de Melo Rêgo Moacyr Jesus, Silva Guimarães Gonçalves Rafaela, Galdino da Rocha Pitta Marina, Branco Pinto Duarte Angela Luzia, Galdino da Rocha Pitta Maira
Аннотация
BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, fibrosis, and dysregulation of the immune system. The therapeutic options available for SSc have limited efficacy, and there is a clear need for new pharmacological alternatives. Thiazolidinediones (TZD) are molecules that have therapeutic potential for SSc due to their pharmacological properties. In this study, we aimed to evaluate the immunomodulatory activity of a new TZD analogue (LPSF/CR-35) in peripheral blood mononuclear cells (PBMC) from SSc patients.
MATERIALS AND METHODS: PBMC response to LPSF/CR-35 (100µM) was examined from SSc patients (n = 19) and healthy control subjects (n = 8) following PBMC stimulation with anti-CD3/CD28. Cytokines (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17 A) and chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in PBMC culture supernatants by cytometric bead array (CBA). In silico analyses were performed to evaluate the binding affinity of LPSF/CR-35 to peroxisome proliferator-activated receptor gamma (PPARγ).
RESULTS: LPSF/CR-35 treatment significantly reduced the secretion of IL-17 A (p = 0.02), IL-10 (p = 0.001), IL-4 (p = 0.04), CCL2/MCP-1 (p = 0.003), and CXCL8/IL-8 (p = 0.03), while increasing TNF levels (p = 0.004) in PBMCs from SSc patients. Molecular docking predicted high binding affinity of both E (-9.987 kcal/mol) and Z (-9.992 kcal/mol) isomers of LPSF/CR-35 to PPARγ, supporting a possible PPARγ-dependent mechanism.
CONCLUSIONS: Our results indicate that LPSF/CR-35 modulates key cytokines and chemokines involved in SSc immunopathology, possibly through PPARγ activation. These findings support the potential of LPSF/CR-35 as an immunomodulatory agent in SSc. Further studies are needed to elucidate its effects on fibrosis and confirm its mechanism of action.
MATERIALS AND METHODS: PBMC response to LPSF/CR-35 (100µM) was examined from SSc patients (n = 19) and healthy control subjects (n = 8) following PBMC stimulation with anti-CD3/CD28. Cytokines (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17 A) and chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in PBMC culture supernatants by cytometric bead array (CBA). In silico analyses were performed to evaluate the binding affinity of LPSF/CR-35 to peroxisome proliferator-activated receptor gamma (PPARγ).
RESULTS: LPSF/CR-35 treatment significantly reduced the secretion of IL-17 A (p = 0.02), IL-10 (p = 0.001), IL-4 (p = 0.04), CCL2/MCP-1 (p = 0.003), and CXCL8/IL-8 (p = 0.03), while increasing TNF levels (p = 0.004) in PBMCs from SSc patients. Molecular docking predicted high binding affinity of both E (-9.987 kcal/mol) and Z (-9.992 kcal/mol) isomers of LPSF/CR-35 to PPARγ, supporting a possible PPARγ-dependent mechanism.
CONCLUSIONS: Our results indicate that LPSF/CR-35 modulates key cytokines and chemokines involved in SSc immunopathology, possibly through PPARγ activation. These findings support the potential of LPSF/CR-35 as an immunomodulatory agent in SSc. Further studies are needed to elucidate its effects on fibrosis and confirm its mechanism of action.