Pharmacological Effects of SB 220025, a Selective Inhibitor of P38 Mitogen-Activated Protein Kinase, in Angiogenesis and Chronic Inflammatory Disease Models
- Jeffrey R. Jackson1,
- Brian Bolognese1,
- Leonard Hillegass1,
- Shouki Kassis2,
- Jerry Adams3,
- Don E. Griswold1 and
- James D. Winkler1
- 1From the Departments of Immunopharmacology (J.R.J., B.B., L.H., D.E.G., J.D.W.), 2Cellular Biochemistry (S.K.) and 3Medicinal Chemistry (J.A.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania
Abstract
Chronic inflammatory diseases often are accompanied by intense angiogenesis, supporting the destructive proliferation of inflammatory tissues. A model of inflammatory angiogenesis is the murine air pouch granuloma, which has a hyperangiogenic component. In this model, we explored the regulation of inflammatory angiogenesis using SB 220025, a specific inhibitor of human p38 mitogen-activated protein (MAP) kinase, with an IC50 value of 60 nM and 50- to 1000-fold selectivity vs. other kinases tested. In vivo, this compound reduced the lipopolysaccharide-induced production of tumor necrosis factor at an ED50 value of 7.5 mg/kg. In the inflammatory angiogenesis model, over the course of granuloma development, we observed elevated levels of interleukin-1β and tumor necrosis factor-α during the chronic inflammatory phase when intense angiogenesis occurs. SB 220025 at 30 mg/kg b.i.d. p.o. was able to greatly reduce the expression of these cytokines and inhibit angiogenesis by ≈40%. To further study the effects of p38/CSBP MAP kinase inhibition in angiogenesis-dependent chronic inflammatory disease, SB 220025 was tested in murine collagen-induced arthritis. In this model, SB 220025 was able to prevent the progression of established arthritis. Thus, this p38/CSBP MAP kinase inhibitor, which can reduce inflammatory cytokine production and inhibit angiogenesis, is an effective treatment for chronic proliferative inflammatory disease.
Footnotes
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Send reprint requests to: Dr. Jeffrey R. Jackson, SmithKline Beecham Pharmaceuticals, Immunopharmacology, UW2532, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail:Jeffrey-R-Jackson{at}SBPHRD.com
- Abbreviations:
- CSBP
- CSAID™ binding protein
- EGFR
- epidermal growth factor receptor
- Erk
- extracellular regulated kinase
- FGF
- fibroblast growth factor
- GM-CSF
- granulocyte/macrophage colony-stimulating factor
- ELISA
- enzyme-linked immunosorbent assay
- IL
- interleukin
- LPS
- lipopolysaccharide
- MAP
- mitogen-activated protein
- PK
- protein kinase
- TNF
- tumor necrosis factor
- VEGF
- vascular endothelial growth factor
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- Received June 11, 1997.
- Accepted October 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
