N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis
Ying-Li Yang , Ning Yao , Shang-Qing Ge , Biao Song , Han Xu , Zeng Li , Xiao-Feng Li , Jun Li
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引用次数: 0
Abstract
Background
Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms.
Methods
We screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1.
Results
Among a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS.
Conclusion
QS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.
期刊介绍：
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.
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