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The Journal of Immunology, 1999, 163: 3459-3467.
Copyright © 1999 by The American Association of Immunologists

A Novel Mechanism of Action of Chemically Modified Tetracyclines: Inhibition of COX-2-Mediated Prostaglandin E2 Production

Rajesh N. Patel1,*, Mukundan G. Attur1,*, Mandar N. Dave*, Indravadan V. Patel*, Steven A. Stuchin{dagger}, Steven B. Abramson*,{ddagger} and Ashok R. Amin2,*,{ddagger},§

Departments of * Rheumatology and {dagger} Orthopedic Surgery, Hospital for Joint Diseases, New York, NY 10003; and Departments of {ddagger} Pathology and § Medicine and Kaplan Cancer Center, New York University Medical Center, New York, NY 10016

Tetracyclines (doxycycline and minocycline) inhibit inducible NO synthase expression and augment cyclooxygenase (COX)-2 expression and PGE2 production. In contrast, chemically modified tetracyclines (CMTs), such as CMT-3 and -8 (but not CMT-1, -2, and -5), that lack antimicrobial activity, inhibit both NO and PGE2 production in LPS-stimulated murine macrophages, bovine chondrocytes, and human osteoarthritis-affected cartilage, which spontaneously produces NO and PGE2 in ex vivo conditions. Furthermore, CMT-3 augments COX-2 protein expression but inhibits net PGE2 accumulation. This coincides with the ability of CMT-3 and -8 to inhibit COX-2 enzyme activity in vitro. The action of CMTs is distinct from that observed with tetracyclines because 1) CMT-3-mediated inhibition of PGE2 production coincides with modification of COX-2 protein, which is distinct from the nonglycosylated COX-2 protein generated in the presence of tunicamycin, as observed by Western blot analysis and 2) CMT-3 and -8 have no significant effect on COX-2 mRNA accumulation. In contrast, CMT-3 and -8 do not inhibit COX-1 expression in A549 human epithelial cells at the level of protein and mRNA accumulation or modification of COX-1 protein. CMT-3 and -8 inhibit the sp. act. of COX-2 (but not COX-1) in cell-free extracts. These results demonstrate differential action of CMT-3 (Metastat) on COX-1 and -2 expression, which is distinct from other tetracyclines.




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