Characterization of pristane-induced arthritis, a murine model of chronic disease: response to antirheumatic agents, expression of joint cytokines, and immunopathology.
OBJECTIVE
To characterize chronic murine pristane-induced arthritis (PIA) with regard to the response to antirheumatic agents, expression levels of proinflammatory cytokines, and immunopathologic features.


METHODS
Male DBA/1 mice were injected intraperitoneally with pristane oil to induce a chronic polyarthritis, which was monitored by visual scoring. Serum antibody and splenocyte responses to a panel of putative joint-derived autoantigens were measured. Whole paws were evaluated postmortem for changes in the levels of proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-6 by enzyme-linked immunosorbent assay, and standard histopathology techniques were used to determine joint structural changes. Therapeutic studies were performed for up to 8 weeks of dosing with prednisolone, methotrexate, 3 nonsteroidal antiinflammatory drugs (celecoxib, diclofenac, and indomethacin), a p38 MAPK inhibitor, SB242235, and human soluble TNF receptor (sTNFR; etanercept) and murine sTNFR fusion proteins.


RESULTS
Antibody and cellular responses to the putative joint autoantigens revealed a broad extent of autoimmunity in PIA. TNFalpha, IL-1beta, and IL-6 were all persistently up-regulated in PIA joints. Prednisolone, methotrexate, celecoxib, indomethacin, and SB242235 all significantly reduced the arthritis scores. Etanercept was ineffective in reducing the arthritis scores, whereas murine sTNFR produced a significant, but nonsustained, benefit. Only prednisolone significantly reduced the expression of TNFalpha, IL-1beta, and IL-6 in the joints. Prednisolone and methotrexate demonstrated the most effective joint protection.


CONCLUSIONS
We have markedly extended the characterization of PIA as a murine model of chronic inflammatory arthritis by demonstrating cellular and humoral autoantigenicity, elevation of clinically precedented joint cytokines, and variation in the response to several antirheumatic therapies. PIA offers significant potential for the long-term study of immunopathologic mechanisms and novel therapies in rheumatoid arthritis.
GlaxoSmithKline Medicines Research Centre, Stevenage, UK. Chris.5.Patten@GSK.com
Christopher
C
Patten
Katherine
K
Bush
Inma
I
Rioja
Rebecca
R
Morgan
Paul
P
Wooley
John
J
Trill
Paul
P
Life
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000032:analysis; D002908:Chronic Disease; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D007596:Joints / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D011239:Prednisolone / Q000627:therapeutic use; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D001323:Autoantibodies; D007375:Interleukin-1; D015850:Interleukin-6; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; C009042:pristane; D011239:Prednisolone; D048051:p38 Mitogen-Activated Protein Kinases; D008727:Methotrexate