Denervated Schwann Cells Attract Macrophages by Secretion of Leukemia Inhibitory Factor (LIF) and Monocyte Chemoattractant Protein-1 in a Process Regulated by Interleukin-6 and LIF

Overview

Journal J Neurosci

Specialty Neurology

Date 2002 Aug 2

PMID 12151548

Citations 143

Authors

George K Tofaris

Paul H Patterson

Kristjan R Jessen

Rhona Mirsky

Affiliations

Soon will be listed here.

Abstract

Injury to peripheral nerves results in the infiltration of immune cells, which remove axonal- and myelin-derived material. Schwann cells could play a key role in this process by regulating macrophage infiltration. We show here that medium conditioned by primary denervated Schwann cells or the Schwannoma cell line RN22 produces chemotactic activity for macrophages. The presence of blocking antibodies to macrophage chemoattractant protein-1 (MCP-1) or leukemia inhibitory factor (LIF) reduced this activity to approximately 35 and 65% of control levels, respectively, and only 15% remained in the presence of both antibodies. The presence of chemotactic LIF in Schwann cell-conditioned medium was confirmed by using cells from lif-/- mice. Although interleukin-6 (IL-6) is not itself a chemotactic factor, we found that medium from il-6-/- nerves showed only 40% of the activity secreted by wild-type nerves. Furthermore, IL-6 rapidly induced LIF mRNA in primary Schwann cells, and LIF rapidly induced MCP-1 mRNA expression. Treatment of RN22 Schwannoma cells with IL-6 or LIF enhanced the secretion of the chemotactic activity of these cells. These observations show that Schwann cells attract macrophages by secreting MCP-1 and LIF. They also provide evidence for an autocrine-signaling cascade involving IL-6, LIF, and MCP-1, which amplifies the Schwann cell-derived chemotactic signals gradually, in agreement with the delayed entry of macrophages to injured nerves.

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References

Fujioka T, Kolson D, Rostami A . Chemokines and peripheral nerve demyelination. J Neurovirol. 1999; 5(1):27-31. DOI: 10.3109/13550289909029742. View

Meier C, Parmantier E, Brennan A, Mirsky R, Jessen K . Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB. J Neurosci. 1999; 19(10):3847-59. PMC: 6782711. View

Gadient R, Patterson P . Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130 transducing receptor: roles in inflammation and injury. Stem Cells. 1999; 17(3):127-37. DOI: 10.1002/stem.170127. View

Dowsing B, Morrison W, Nicola N, Starkey G, Bucci T, Kilpatrick T . Leukemia inhibitory factor is an autocrine survival factor for Schwann cells. J Neurochem. 1999; 73(1):96-104. DOI: 10.1046/j.1471-4159.1999.0730096.x. View

Jessen K, Mirsky R . Schwann cells and their precursors emerge as major regulators of nerve development. Trends Neurosci. 1999; 22(9):402-10. DOI: 10.1016/s0166-2236(98)01391-5. View

Rutkowski J, Tuite G, Lincoln P, Boyer P, Tennekoon G, Kunkel S . Signals for proinflammatory cytokine secretion by human Schwann cells. J Neuroimmunol. 1999; 101(1):47-60. DOI: 10.1016/s0165-5728(99)00132-0. View

Sugiura S, Lahav R, Han J, KOU S, Banner L, De Pablo F . Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. Eur J Neurosci. 2000; 12(2):457-66. DOI: 10.1046/j.1460-9568.2000.00922.x. View

Siebert H, Sachse A, Kuziel W, Maeda N, Bruck W . The chemokine receptor CCR2 is involved in macrophage recruitment to the injured peripheral nervous system. J Neuroimmunol. 2000; 110(1-2):177-85. DOI: 10.1016/s0165-5728(00)00343-x. View

Galimi F, Cottone E, Vigna E, Arena N, Boccaccio C, Giordano S . Hepatocyte growth factor is a regulator of monocyte-macrophage function. J Immunol. 2001; 166(2):1241-7. DOI: 10.4049/jimmunol.166.2.1241. View

10.

Zhu M, Oishi K, Lee S, Patterson P . Studies using leukemia inhibitory factor (LIF) knockout mice and a LIF adenoviral vector demonstrate a key anti-inflammatory role for this cytokine in cutaneous inflammation. J Immunol. 2001; 166(3):2049-54. DOI: 10.4049/jimmunol.166.3.2049. View

11.

Subang M, Richardson P . Influence of injury and cytokines on synthesis of monocyte chemoattractant protein-1 mRNA in peripheral nervous tissue. Eur J Neurosci. 2001; 13(3):521-8. DOI: 10.1046/j.1460-9568.2001.01425.x. View

12.

Hurst S, Wilkinson T, McLoughlin R, Jones S, Horiuchi S, Yamamoto N . Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 2001; 14(6):705-14. DOI: 10.1016/s1074-7613(01)00151-0. View

13.

Marin V, Montero-Julian F, Gres S, Boulay V, Bongrand P, Farnarier C . The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J Immunol. 2001; 167(6):3435-42. DOI: 10.4049/jimmunol.167.6.3435. View

14.

Mack T, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D . Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci. 2002; 4(12):1199-206. DOI: 10.1038/nn770. View

15.

Lunn E, Perry V, Brown M, Rosen H, Gordon S . Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve. Eur J Neurosci. 1989; 1(1):27-33. DOI: 10.1111/j.1460-9568.1989.tb00771.x. View

16.

Perry V, Brown M, Lunn E, Tree P, Gordon S . Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve. Eur J Neurosci. 1990; 2(9):802-8. DOI: 10.1111/j.1460-9568.1990.tb00472.x. View

17.

Perry V, Brown M . Role of macrophages in peripheral nerve degeneration and repair. Bioessays. 1992; 14(6):401-6. DOI: 10.1002/bies.950140610. View

18.

Villiger P, 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; 90(2):488-96. PMC: 443125. DOI: 10.1172/JCI115885. View

19.

Patterson P, Fann M . Further studies of the distribution of CDF/LIF mRNA. Ciba Found Symp. 1992; 167:125-35; discussion 135-40. DOI: 10.1002/9780470514269.ch8. View

20.

Stewart C, Kaspar P, Brunet L, Bhatt H, Gadi I, Kontgen F . Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992; 359(6390):76-9. DOI: 10.1038/359076a0. View