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 examine the antiinflammatory properties of minocycline. Administration of oral 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 splenocytes exhibiting a rise in free intracellular calcium concentration ([Ca2+]i) following concanavalin A stimulation (P < 0.05 in adjuvant and P < 0.01 in collagen). This enhancement was mitogen dose-dependent and supported exclusively by extracellular Ca2+. Resting [Ca2+]i levels were unaffected by minocycline and predominantly the CD4+ subset was involved. No changes were observed in weight, IgG antibodies to collagen, synoviocyte release of collagenase and prostaglandin E2, acute inflammation in an air-pouch system, or cell surface expression of activation markers (interleukin-2 and transferrin receptors) by splenocytes or lymph node cells. As a controlled [Ca2+]i rise is a critical event in normal T cell activation, minocycline's antiarthritic profile in vivo may relate to perturbed Ca2+ influx during T cell activation, an alteration that could promote the development of clinical tolerance to otherwise arthritogenic stimuli.
Sewell
K L
KL
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Breedveld
F
F
Furrie
E
E
O'Brien
J
J
Brinckerhoff
C
C
Dynesius-Trentham
R
R
Nosaka
Y
Y
Trentham
D E
DE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003094:Collagen / Q000276:immunology; D008213:Lymphocyte Activation; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001323:Autoantibodies; D003094:Collagen; D008911:Minocycline; D002118:Calcium