Summary
Leukaemia inhibitory factor (LIF) is a secretory glycoprotein produced by tumour, mesenchymal and haemopoietic cells. LIF has been found to have pleiotropic actions that include the capacity to regulate cell differentiation, promote acute-phase protein synthesis and stimulate calcium release in bone explants. In view of its similarity to other cytokines that affect cartilage metabolism, the effects of LIF on proteoglycan resorption were examined in pig cartilage explants. Endotoxinfree recombinant mouse LIF was found to produce a dose-dependent increase in sulphated glycosaminoglycan (S-GAG) release (ED50=123 U/ml, approx. 25–50 pM). Statistically significant stimulation was observed with doses of 100 U/ml or greater. When pig cartilage was stimulated with maximum concentrations of LIF and either interleukin 1α (IL-1α), interleukin 1β (IL-1β) or tumour necrosis factor α (TNFα), in each case a significantly greater release of S-GAGs was observed than with the respective cytokines alone (P<0.05). Comparison of the areas under the curves showed that the action of LIF was additive, and not synergistic with other catabolic cytokines. Dose-response studies showed that transforming growth factor β (TGFβ) produced a partial inhibition of LIF-stimulated release of S-GAGs (ED50=4.5 U/ml). Statistically significant inhibition was observed with doses of 2U/ml or greater. These results showed that LIF stimulated proteoglycan resorption in vitro and that this effect was modulated by other cytokines. Whether LIF contributes to the progressive destruction of cartilage in septic or chronic inflammatory arthritis remains to be determined.
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Hilton DJ, Nicola NA, Gough NM, Metcalf D (1988) Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-inducing activity on murine myeloid leukaemic cell lines. J Biol Chem 263:9238–9243
Hilton DJ, Nicola NA, Metcalf D (1988) Purification and characterization of a murine leukaemia inhibitory factor from Krebs ascites cells. Anal Biochem 173:359–367
Abe E, Tanaka H, Ishimi Y, Miyaura C, Hayashi T, Nagasawa H, Tomida M, Yamaguchi Y, Hozumi M, Suda T (1986) Differentiation-inducing factor purified from conditioned medium of mitogen-treated spleen cell cultures stimulates bone resorption. Proc Natl Acad Sci USA 83:5958–5962
Tomida M, Yamamoto-Yamaguchi Y, Hozumi M (1984) Purification of a factor inducing differentiation of mouse myeloid M1 cells from conditioned medium of mouse fibroblast L929 cells. J Biol Chem 259:10978–10982
Koopman P, Cotton RGH (1984) A factor produced by feeder cells which inhibits embryonal carcinoma cell differentiation: Characterization and partial purification. Exp Cell Res 154:233–242
Smith AG, Hooper ML (1987) Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol 121:1–9
Godard A, Gascan H, Naulet J, Peyrat MA, Jacques Y, Soulillou JP, Moreau JF (1988) Biochemical characterization and purification of HILDA, a human lymphokine active on eosinophils and bone marrow cells. Blood 71:1618–1623
Gough NM, Williams RL (1989) The pleiotropic actions of leukaemia inhibitory factor. Cancer Cells 1:77–80
Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690
Gearing DP, Gough NM, King JA, Hilton DJ, Nicola NA, Simpson RJ, Nice EC, Kelso A, Metcalf D (1987) Molecular clonign and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J 6:3995–4002
Gearing DP, King JA, Gough NM (1988) Complete sequence of murine myeloid leukaemia inhibitory factor (LIF). Nucleic Acids Res 16:9857
Gough NM, Gearing DP, King JA, Wilson TA, Hilton DJ, Nicola NA, Metcalf D (1988) Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukaemia inhibitory factor. Proc Natl Acad Sci USA 85:2623–2627
Moreau JF, Donaldson DD, Bennett F, Witek-Gianotti J, Clark SC, Wong GG (1988) Leukaemia inhibitory factor is identical to the myeloid growth factor interleukin for DA cells. Nature 336:690–692
Reid IR, Lowe C, Cornish J, Skinner SJM, Hilton DJ, Willson TA, Gearing DP, Martin TJ (1990) Leukaemia inhibitory factor: A novel bone-active cytokine. Endocrinology 126:1416–1420
Baumann H, Wong GG (1989) Hepatocyte-stimulating factorIII shares structural and functional identity with leukaemia inhibitory factor. J Immunol 143:1163–1167
Farndale RW, Buttle DJ, Barrett AJ (1985) Improved quantitation and discrimination of sulphated glycosaminoglycans by the use of dimethylmethylene blue. Biochim Biophys Acta 883:173–177
Meddings JB, Scott RB, Fick GH (1989) Analysis and comparison of sigmoidal curves: application to dose-response data. Am J Physiol 257:982–989
Harris ED (1990) Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 322:1277–1289
Fell HB, Jubb RW (1977) The effect of synovial tissue on the breakdown of articular cartilage in organ culture. Arthritis Rheum 20:1359–1371
Dingle JT, Saklatvala J, Hembry R, Tyler J (1979) A cartilage catabolic factor from synovium. Biochem J 184:177–180
Saklatvala J, Sarsfield SJ, Townsend Y (1985) Pig interleukin 1. Purification of two immunologically different leukocyte proteins that cause cartilage resorption, lymphocyte activation and fever. J Exp Med 162:1208–1222
Saklatvala J (1986) Tumour necrosis factor stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322:547–549
Murphy G, Docherty AJP, Hembry RM, Reynolds JJ (1991) Metalloproteinases and tissue damage. Br J Rheumatol 30 [Suppl 1]:25–31
Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336–340
Eisenberg SP, Evan RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC (1990) Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343:341–346
Carter DB, Deibel MR, Dunn CJ, Tomich C-SC, Laborde AL, Slightom JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN, Harris PKW, Yem AW, Waszak GA, Chosay JG, Sieu LC, Hardee MM, Zurcher-Neely HA, Reardon IM, Heinrikson RL, Truesdell SE, Shelly JA, Eessalu TE, Taylor BM, Tracey DE (1990) Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344:633–638
Smith RJ, Chin JE, Sam LM, Justen JM (1991) Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1 —stimulated cartilage erosion and chondrocyte responsiveness. Arthritis Rheum 34:78–83
Henderson B, Thompson RC, Hardingham T, Lewthwaite J (1991) Inhibition of interleukin-1 — induced synovitis and articular cartilage proteoglycan loss in the rabbit knee by recombinant human interleukin-1 receptor antagonist. Cytokine 3: 246–249
Metcalf D (1989) Suppression of myeloid leukaemic cells by normal hemopoietic regulators. In: Proceedings of the Mochida memorial symposium, Recent progress in cytokine research. pp 119–134
Hollander AP, Atkins RM, Eastwood DM, Dieppe PA, Elson CJ (1991) Degradation of human cartilage by synovial fluid but not cytokines in vitro. Ann Rheum Dis 50:57–58
Waring PM, Carroll GJ, Kandiah DA, Buirski G Leukemia inhibitory factor levels are elevated in synovial fluid from patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum (in press)
Dubois CM, Ruscetti FW, Palaszynski EW, Falk LA, Oppenheim JJ, Keller JR (1990) Transforming growth factor β is a potent inhibitor of interleukin-1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J Exp Med 172:737–744
Tyler JA (1988) The influence of IL1 and IGF1 in the integrity of cartilage matrix. In Glauert AM (ed) The control of tissue damage. Elsevier, Amsterdam, pp 197–214
Dingle JT, Horner A, Shield M (1991) The sensitivity of synthesis of human cartilage matrix to inhibition of IL-1 suggests a mechanism for the development of osteoarthritis. Cell Biochem Func 9:99–102
Nietfeld JJ, Wibrink B, Den Otter W, Huber J, Huber-Bruning O (1990) The effect of human interleukin 1 on proteoglycan metabolism in human and porcine cartilage explants. J Rheumatol 17:818–826
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Carroll, G.J., Bell, M.C. Leukaemia inhibitory factor stimulates proteoglycan resorption in porcine articular cartilage. Rheumatol Int 13, 5–8 (1993). https://doi.org/10.1007/BF00290327
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DOI: https://doi.org/10.1007/BF00290327