The tyrosine kinase inhibitor tyrphostin AG126 reduces activation of inflammatory cells and increases Foxp3+regulatory T cells during pathogenesis of rheumatoid arthritis.
Protein tyrosine kinases are key mediators of the signal transduction cascades that control expression of many genes involved in the induction of inflammation caused by arthritis. Here we investigate the effect of the tyrosine kinase inhibitor tyrphostin AG126 on a mouse model of adjuvant-induced arthritis (AIA). We report that when given at 5mg/kg i.p. every 48h from days 0-21, AG126 exerts potent anti-arthritic effects. Further, we investigated the role of AG126 on the key mediators of arthritic inflammation, namely, edema, arthritic score, presence of immunophenotypes including Foxp3+, CD4+Foxp3+, and CD25+Foxp3+T regulatory (Treg) cells, as well as pro- and anti-inflammatory mediators. AG126 treatment significantly attenuated the severity of AIA and caused a substantial reduction in the percentage of CD2+, CD3+, CD4+, CD8+, CD23+, CD80+, CD86+CD122+, CD195+, TCRβ+, and GITR+cells in whole blood. Moreover, administration of AG126 under arthritis-inducing conditions resulted in suppression of IL-17A+, IFN-γ+, CD4+and CD25+populations while causing an increase in the Foxp3+, CD4+Foxp3+, and CD25+Foxp3+Treg populations in the spleen. In addition, RT-PCR analysis revealed increased expression of CD4, CD8, IL-17A, IFN-γ, TNF-α, and NF-κB p65 mRNAs and decreased IL-4 mRNA in the arthritic control (AC) mice, while treatment of animals with AG126 reversed these effects. Western blot analysis confirmed the decreased expression of IL-17, GITR, NF-κB p65 proteins and increased Foxp3 and IL-4 proteins following AG126 treatment of knee tissue. Thus, our findings provide new evidence that inhibition of protein tyrosine kinase activity decreases the progression of arthritis.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: s_fayazahmad@yahoo.com.
Sheikh Fayaz
SF
Ahmad
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Mushtaq Ahmad
MA
Ansari
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Ahmed
A
Nadeem
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Center, Cairo, Egypt.
Khairy M A
KM
Zoheir
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Saleh A
SA
Bakheet
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Othman A
OA
Al-Shabanah
Department of Pathology, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
Ammar Cherkess
AC
Al Rikabi
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.
Sabry M
SM
Attia
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015153:Blotting, Western; D016207:Cytokines / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D020032:Tyrphostins / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins
Adjuvant induced arthritis; Immunophenotypes; Inflammatory cytokines; Regulatory T cells; Tyrosine kinase inhibitor