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J Clin Invest. Sep 1992; 90(3): 888–896.
PMCID: PMC329943

Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis.

Abstract

This study reports on leukemia inhibitory factor (LIF) in human articular connective tissues. Biologically active LIF is present in synovial fluids from patients with osteoarthritis and at higher titers in samples from patients with rheumatoid arthritis. Cultured human synoviocytes and articular chondrocytes produced biologically active LIF and synthesized and secreted LIF proteins that migrated in SDS PAGE at approximately 43 kD. This was increased after stimulation with IL-1 beta. Chondrocytes in serum-containing cultures expressed the 4.2-kb LIF mRNA. IL-1 beta, LPS, and to a lesser extent tumor necrosis factor-alpha induced LIF gene expression. LIF autoinduced its mRNA and this provides evidence for an effect of this cytokine on function of joint tissue cells. Among a series of growth factors tested, transforming growth factor (TGF beta), including the isoforms TGF-beta1, TGF-beta 2, and TGF-beta 3, platelet-derived growth factor, basic fibroblast growth factor, and insulin-like growth factor induced this cytokine gene but differed with respect to the duration of their effects. Cultured synoviocytes expressed the LIF gene in response to the same set of peptide regulatory factors. Analysis of signal transduction pathways showed that PMA increased LIF mRNA, whereas calcium ionophore and cAMP had no detectable effects. Cycloheximide was a potent LIF mRNA inducer and dexamethasone inhibited LIF induced by PMA or IL-1 beta. Cartilage organ cultures and synovial tissues stimulated with IL-1 expressed high levels of LIF mRNA as demonstrated by in situ hybridization. These results identify LIF as a new cytokine that is produced by joint tissue cells and is overexpressed in arthritis. The induction of this cytokine by factors that are present during joint inflammation and the effects of LIF on connective tissue cells suggest that LIF is a mediator that can contribute to the pathogenesis of arthritis.

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  • Mizel SB, Dayer JM, Krane SM, Mergenhagen SE. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin 1). Proc Natl Acad Sci U S A. 1981 Apr;78(4):2474–2477. [PMC free article] [PubMed]
  • Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. [PMC free article] [PubMed]
  • Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7;322(6079):547–549. [PubMed]
  • Le J, Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987 Mar;56(3):234–248. [PubMed]
  • Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed]
  • Lotz M, Guerne PA. Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J Biol Chem. 1991 Feb 5;266(4):2017–2020. [PubMed]
  • Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. [PMC free article] [PubMed]
  • Zuraw BL, Lotz M. Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. J Biol Chem. 1990 Jul 25;265(21):12664–12670. [PubMed]
  • Guerne PA, Lotz M. Interleukin-6 and transforming growth factor-beta synergistically stimulate chondrosarcoma cell proliferation. J Cell Physiol. 1991 Oct;149(1):117–124. [PubMed]
  • Oppenheim JJ, Zachariae CO, Mukaida N, Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. [PubMed]
  • Saxne T, Palladino MA, Jr, Heinegård D, Talal N, Wollheim FA. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. [PubMed]
  • Fava R, Olsen N, Keski-Oja J, Moses H, Pincus T. Active and latent forms of transforming growth factor beta activity in synovial effusions. J Exp Med. 1989 Jan 1;169(1):291–296. [PMC free article] [PubMed]
  • Lotz M, Kekow J, Carson DA. Transforming growth factor-beta and cellular immune responses in synovial fluids. J Immunol. 1990 Jun 1;144(11):4189–4194. [PubMed]
  • Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest. 1989 Feb;83(2):585–592. [PMC free article] [PubMed]
  • Firestein GS, Xu WD, Townsend K, Broide D, Alvaro-Gracia J, Glasebrook A, Zvaifler NJ. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988 Nov 1;168(5):1573–1586. [PMC free article] [PubMed]
  • Seitz M, Dewald B, Gerber N, Baggiolini M. Enhanced production of neutrophil-activating peptide-1/interleukin-8 in rheumatoid arthritis. J Clin Invest. 1991 Feb;87(2):463–469. [PMC free article] [PubMed]
  • Lotz M, Terkeltaub R, Villiger PM. Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. J Immunol. 1992 Jan 15;148(2):466–473. [PubMed]
  • Villiger PM, Terkeltaub R, Lotz M. Monocyte chemoattractant protein-1 (MCP-1) expression in human articular cartilage. Induction by peptide regulatory factors and differential effects of dexamethasone and retinoic acid. J Clin Invest. 1992 Aug;90(2):488–496. [PMC free article] [PubMed]
  • Gearing DP. Leukemia inhibitory factor: does the cap fit? Ann N Y Acad Sci. 1991;628:9–18. [PubMed]
  • Metcalf D. The leukemia inhibitory factor (LIF). Int J Cell Cloning. 1991 Mar;9(2):95–108. [PubMed]
  • Metcalf D, Hilton DJ, Nicola NA. Clonal analysis of the actions of the murine leukemia inhibitory factor on leukemic and normal murine hemopoietic cells. Leukemia. 1988 Apr;2(4):216–221. [PubMed]
  • Moreau JF, Donaldson DD, Bennett F, Witek-Giannotti J, Clark SC, Wong GG. Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells. Nature. 1988 Dec 15;336(6200):690–692. [PubMed]
  • Abe T, Murakami M, Sato T, Kajiki M, Ohno M, Kodaira R. Macrophage differentiation inducing factor from human monocytic cells is equivalent to murine leukemia inhibitory factor. J Biol Chem. 1989 May 25;264(15):8941–8945. [PubMed]
  • Verfaillie C, McGlave P. Leukemia inhibitory factor/human interleukin for DA cells: a growth factor that stimulates the in vitro development of multipotential human hematopoietic progenitors. Blood. 1991 Jan 15;77(2):263–270. [PubMed]
  • Metcalf D, Hilton D, Nicola NA. Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. Blood. 1991 May 15;77(10):2150–2153. [PubMed]
  • Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988 Dec 15;336(6200):688–690. [PubMed]
  • Murphy M, Reid K, Hilton DJ, Bartlett PF. Generation of sensory neurons is stimulated by leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3498–3501. [PMC free article] [PubMed]
  • Yamamori T, Fukada K, Aebersold R, Korsching S, Fann MJ, Patterson PH. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science. 1989 Dec 15;246(4936):1412–1416. [PubMed]
  • Baumann H, Wong GG. Hepatocyte-stimulating factor III shares structural and functional identity with leukemia-inhibitory factor. J Immunol. 1989 Aug 15;143(4):1163–1167. [PubMed]
  • Mori M, Yamaguchi K, Abe K. Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia. Biochem Biophys Res Commun. 1989 May 15;160(3):1085–1092. [PubMed]
  • Metcalf D, Gearing DP. Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5948–5952. [PMC free article] [PubMed]
  • Metcalf D, Gearing DP. A myelosclerotic syndrome in mice engrafted with cells producing high levels of leukemia inhibitory factor (LIF). Leukemia. 1989 Dec;3(12):847–852. [PubMed]
  • Reid LR, Lowe C, Cornish J, Skinner SJ, Hilton DJ, Willson TA, Gearing DP, Martin TJ. Leukemia inhibitory factor: a novel bone-active cytokine. Endocrinology. 1990 Mar;126(3):1416–1420. [PubMed]
  • Rodan SB, Wesolowski G, Hilton DJ, Nicola NA, Rodan GA. Leukemia inhibitory factor binds with high affinity to preosteoblastic RCT-1 cells and potentiates the retinoic acid induction of alkaline phosphatase. Endocrinology. 1990 Oct;127(4):1602–1608. [PubMed]
  • Allan EH, Hilton DJ, Brown MA, Evely RS, Yumita S, Metcalf D, Gough NM, Ng KW, Nicola NA, Martin TJ. Osteoblasts display receptors for and responses to leukemia-inhibitory factor. J Cell Physiol. 1990 Oct;145(1):110–119. [PubMed]
  • Noda M, Vogel RL, Hasson DM, Rodan GA. Leukemia inhibitory factor suppresses proliferation, alkaline phosphatase activity, and type I collagen messenger ribonucleic acid level and enhances osteopontin mRNA level in murine osteoblast-like (MC3T3E1) cells. Endocrinology. 1990 Jul;127(1):185–190. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Villiger PM, Cronin MT, Amenomori T, Wachsman W, Lotz M. IL-6 production by human T lymphocytes. Expression in HTLV-1-infected but not in normal T cells. J Immunol. 1991 Jan 15;146(2):550–559. [PubMed]
  • Kitamura T, Tange T, Terasawa T, Chiba S, Kuwaki T, Miyagawa K, Piao YF, Miyazono K, Urabe A, Takaku F. Establishment and characterization of a unique human cell line that proliferates dependently on GM-CSF, IL-3, or erythropoietin. J Cell Physiol. 1989 Aug;140(2):323–334. [PubMed]
  • Stahl J, Gearing DP, Willson TA, Brown MA, King JA, Gough NM. Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions. J Biol Chem. 1990 May 25;265(15):8833–8841. [PubMed]
  • Lübbert M, Mantovani L, Lindemann A, Mertelsmann R, Herrmann F. Expression of leukemia inhibitory factor is regulated in human mesenchymal cells. Leukemia. 1991 May;5(5):361–365. [PubMed]
  • Anegon I, Moreau JF, Godard A, Jacques Y, Peyrat MA, Hallet MM, Wong G, Soulillou JP. Production of human interleukin for DA cells (HILDA)/leukemia inhibitory factor (LIF) by activated monocytes. Cell Immunol. 1990 Oct 1;130(1):50–65. [PubMed]

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