Leukemia inhibitory factor (LIF) binding protein attenuates the phlogistic and abolishes the chondral effects of LIF in goat joints.
OBJECTIVE
To investigate the ability of murine leukemia inhibitory factor (LIF) binding protein (mLBP) to attenuate the effects of recombinant human LIF (rhLIF) in goat radiocarpal joints in vivo.


METHODS
Endotoxin-free saline (1 ml) containing either 0.5 or 1 microg of rhLIF was injected into the left and right radiocarpal joints of male angora goats. One hour later the right radiocarpal joints were injected with either 1 or 5 microg of naturally occurring mLBP in 1 ml saline, while the left radiocarpal joints (controls) received 1 ml saline vehicle alone. Goat joints were examined for clinical features of inflammation and synovial fluid (SF) was aspirated on Day 0 (before injection) and Days 2 and 6 postinjection. Leukocyte counts and concentrations of keratan sulfate were determined in the SF. Proteoglycan synthesis and proteoglycan content of cartilage was determined ex vivo in cartilage explants obtained at Day 6.


RESULTS
Preliminary time course studies in vitro showed that mLBP had to be added to cartilage explant cultures within 1 h of rhLIF for effective antagonism to occur. In joints injected with either 0.5 or 1 microg rhLIF significant increases in swelling, effusion volume, leukocyte counts, and SF keratan sulfate concentrations were observed relative to controls. Statistically significant depressions of ex vivo proteoglycan synthesis and in proteoglycan content of articular cartilage were also observed relative to controls. In joints injected with 1 microg rhLIF followed by 1 microg mLBP, statistically significant improvement was only observed in the rate of ex vivo cartilage proteoglycan synthesis. The observed rate did not differ significantly from that obtained in joints treated with vehicle alone. In contrast, in joints injected with 0.5 microg rhLIF followed by 5 microg mLBP, statistically significant improvement was observed in all variables. Treatment with 5 microg mLBP effectively negated the effects of rhLIF on joint swelling, effusion volume, leukocyte infiltration, and cartilage proteoglycan catabolism.


CONCLUSIONS
Murine LBP has the ability to attenuate the phlogistic effects of rhLIF in radiocarpal joints of goats and also abolishes the stimulatory effect of rhLIF on cartilage proteoglycan catabolism and depression of ex vivo proteoglycan synthesis. These antiinflammatory and chondral effects suggest that a humanized derivative of mLBP could be a clinically useful antagonist for LIF in inflammatory diseases.
Bell
M
M
Department of Rheumatology and the Research Centre, Royal Perth Hospital, Australia.
Carroll
G J
GJ
Chapman
H
H
Layton
M
M
Mills
J
J
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D002358:Cartilage, Articular / Q000187:drug effects*; D006041:Goats; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007270:Injections, Intra-Articular; D015850:Interleukin-6; D007596:Joints / Q000503:physiopathology; D007632:Keratan Sulfate / Q000096:biosynthesis / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D007958:Leukocyte Count / Q000187:drug effects; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D011509:Proteoglycans; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins; D007632:Keratan Sulfate