title: STA-21, a STAT-3 inhibitor, attenuates the development and progression of inflammation in collagen antibody-induced arthritis.
abstract: We set out to investigate the influence of STA-21, a dynamic STAT-3 inhibitor, on the expansion and progression of rheumatoid arthritis (RA), and to determine its potential mechanisms of action in a mouse model of collagen antibody-induced arthritis (CAIA). To this end, arthritis was induced via intravenous (IV) injection of Balb/c mice with a cocktail of antibodies directed against type II collagen (1.5μg/mouse, IV), followed by lipopolysaccharide (LPS) at a dose of (25μg/mouse, i.p.) on day 3. Mice were then left untreated or were simultaneously treated with STA-21 (0.5mg/kg, i.p., once daily for 2 weeks) followed by evaluation for clinical and histological features of arthritic inflammation and flow cytometric analysis of cytokines and transcription factors in peripheral blood. STA-21 enhanced the clinical course of arthritis in CAIA mice and decreased CD8+RORγt+and CD8+IL-21+cells while inducing the production of CD8+Foxp3+cells. Furthermore, STA-21 prevented the production of TNF-α and IL-6 in peripheral blood and increased IL-27 production by CD14+cells. Moreover, STA-21 not only regulates Th1/Th2 serum cytokine levels but also the mRNA and protein expression of key factors including NF-κB p65, RORγt, T-bet, IL-4, GATA-3, JAK1, Stat3, and IL-21. Thus, administration of the Stat3 inhibitor STA-21 inhibits cellular signaling pathways and downstream activation of key transcription factors previously shown to play key roles in the pathogenesis of RA. Therefore, these data suggest that STA-21 could be considered as a potential treatment for patients with RA.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: s_fayazahmad@yahoo.com.
authors.forename: Sheikh Fayaz
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mushtaq Ahmad
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cairo, Egypt.
authors.forename: Khairy M A
authors.initials: KMA
authors.lastname: Zoheir
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdulaziz M S
authors.initials: AMS
authors.lastname: Alsaad
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Othman A
authors.initials: OA
authors.lastname: Al-Shabanah
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011083:Polycyclic Compounds; C500947:STA-21; D050796:STAT3 Transcription Factor
keywords: 5-Clone cocktail of monoclonal anti-type II collagen antibodies; Cytokines; Regulatory T cells; STA-21; Transcription factors