THE EFFECT OF MINOCYCLINE IN RAT MODELS OF INFLAMMATORY ARTHRITIS - CORRELATION OF ARTHRITIS SUPPRESSION WITH ENHANCED T-CELL CALCIUM FLUX

Adjuvant and collagen arthritis in the rat are widely accepted T-cell- dependent counterparts of rheumatoid arthritis and were used to examin e the antiinflammatory properties of minocycline, Administration of or al minocycline, a semisynthetic tetracycline, significantly decreased (P < 0.01) the incidence of arthritis in both models. In vivo exposure to minocycline also significantly increased the percentage of splenoc ytes exhibiting a rise in free intracellular calcium concentration ([C a2+](i)) following concanavalin A stimulation (P < 0.05 in adjuvant an d P < 0.01 in collagen). This enhancement was mitogen dose-dependent a nd supported exclusively by extracellular Ca2+. Resting [Ca2+](i) leve ls were unaffected by minocycline and predominantly the CD4(+) subset was involved. No changes were observed in weight, IgG antibodies to co llagen, synoviocyte release of collagenase and prostaglandin E(2), acu te inflammation in an air-pouch system, or cell surface expression of activation markers (interleukin-2 and transferrin receptors) by spleno cytes or lymph node cells. As a controlled [Ca2+](i) rise is a critica l event in normal T cell activation, minocycline's antiarthritic profi le in vivo may relate to perturbed Ca2+ influx during T cell activatio n, an alteration that could promote the development of clinical tolera nce to otherwise arthritogenic stimuli. (C) 1996 Academic Press, Inc.