Pro-inflammatory effects of the aminobisphosphonate ibandronate in vitro and in vivo.
OBJECTIVE
To investigate the effects of the aminobisphosphonate, ibandronate, on the course of joint inflammation in rat antigen-induced arthritis (AIA) and the release of pro-inflammatory cytokines in partially purified human peripheral blood mononuclear cells (PBMC).


METHODS
Rats with AIA received a single intra-articular injection of ibandronate (1 mg) 7 days post-arthritis induction and knee swelling was measured for 7 days thereafter. The effects of ibandronate (300 microg/ml) on PBMC cytokine production and activation marker expression were determined using polymerase chain reaction (PCR)/ELISA and FACS analysis, respectively.


RESULTS
Joint swelling, associated with AIA, was sustained in ibandronate-treated rats compared with saline-treated control rats. Ibandronate stimulated the production of interferon gamma (IFN-gamma) in adherent PBMC, and increased the surface expression of FcgammaRI and HLA DP, DQ, DR on the adherent monocyte population. Activation by lipopolysaccharide (LPS) of PBMC previously incubated with ibandronate led to enhanced levels of tumour necrosis factor alpha (TNF-alpha) secretion, and this could be partially inhibited by neutralizing antibodies to IFN-gamma.


CONCLUSIONS
The enhanced production of TNF-alpha by ibandronate-treated PBMC in vitro involves stimulation of adherent monocytes by IFN-gamma prior to LPS-induced activation. Similar cellular interactions may be involved in the pro-inflammatory effects of ibandronate in vivo.
Richards
P J
PJ
Rheumatology Research Laboratory, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
Amos
N
N
Williams
A S
AS
Williams
B D
BD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology*; D002908:Chronic Disease; D017931:DNA Primers; D004164:Diphosphonates / Q000276:immunology* / Q000494:pharmacology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D000077557:Ibandronic Acid; D066298:In Vitro Techniques; D007270:Injections, Intra-Articular; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics / Q000276:immunology; D007719:Knee Joint / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D017931:DNA Primers; D004164:Diphosphonates; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000077557:Ibandronic Acid