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The Journal of Neuroscience, April 15, 2002, 22(8):3052-3060
The Cytokine Network of Wallerian Degeneration: Tumor Necrosis
Factor- , Interleukin-1, and Interleukin-1
Shlomit
Shamash,
Fanny
Reichert, and
Shlomo
Rotshenker
Department of Anatomy and Cell Biology, Hebrew University-Hadassah
Medical School, and The Eric Roland Center for Neurodegenerative
Diseases, Jerusalem 91120, Israel
Wallerian degeneration (WD) is the inflammatory response of the
nervous system to axonal injury, primarily attributable to the
production of cytokines, the mediator molecules of inflammation. We
presently document the involvement of the inflammatory cytokines TNF , interleukin (IL)-1, and IL-1 in peripheral nerve (PNS) injury in C57/BL/6NHSD (C57/BL) mice that display the normal rapid progression of WD (rapid-WD) and C57/BL/6-WLD/OLA/NHSD mice that display abnormal slow progression of WD (slow-WD). TNF and IL-1 mRNAs were expressed, whereas TNF but not IL-1 protein was
synthesized in intact PNS of C57/BL mice. TNF and IL-1 protein
synthesis and secretion were rapidly upregulated during rapid-WD in
Schwann cells. IL-1 mRNA expression and protein synthesis and
secretion were induced sequentially in Schwann cells with a delay after injury. Thereafter, recruited macrophages contributed to the production of TNF, IL-1, and IL-1, which in turn augmented myelin
phagocytosis by macrophages. Observations suggest that TNF and
IL-1 are the first cytokines with protein production that is
upregulated during rapid-WD. TNF and IL-1 may initiate,
therefore, molecular and cellular events in rapid-WD (e.g., the
production of additional cytokines and NGF). TNF, IL-1, and
IL-1 may further regulate, indirectly, macrophage recruitment,
myelin removal, regeneration, and neuropathic pain. In contrast to
rapid-WD, the production of TNF, IL-1, and IL-1 protein was
deficient in slow-WD, although their mRNAs were expressed. mRNA
expression and protein production of TNF, IL-1, and IL-1 were
differentially regulated during rapid-WD and slow-WD, suggesting that
mRNA expression, by itself, is no indication of the functional
involvement of cytokines in WD.
Key words:
TNF; IL-1; IL-1; Wallerian degeneration; regeneration; pain; Schwann cell; fibroblast; macrophage; myelin; phagocytosis
Copyright © 2002 Society for Neuroscience 0270-6474/02/2283052-09$05.00/0
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