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The Journal of Neuroscience, August 1, 2002, 22(15):6696-6703
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
George K.
Tofaris1,
Paul H.
Patterson2,
Kristjan R.
Jessen3, and
Rhona
Mirsky3
1 Cambridge Centre for Brain Repair and Department of
Neurology, University of Cambridge, Cambridge CB2 2PY, United Kingdom,
2 Division of Biology, California Institute of Technology,
Pasadena, California 91125, and 3 Department of Anatomy and
Developmental Biology, University College London, London WC1E 6BT,
United Kingdom
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 ~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.
Key words:
chemotaxis; macrophage; leukemia inhibitory factor; interleukin 6; regeneration; neuropathy
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156696-08$05.00/0
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