A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive FK506 derivative, JNJ460

R. B. Birge, S. Wadsworth, R. Akakura, H. Abeysinghe, R. Kanojia, M. Macielag, J. Desbarats, M. Escalante, K. Singh, S. Sundarababu, K. Parris, Geoffrey J. Childs, A. August, J. Siekierka, D. E. Weinstein

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

FK506 and its non-immunosuppressive derivatives represent a class of pharmacological agents referred to as immunophilin ligands that have been reported to promote neuroregeneration and survival in several experimental models; however their cellular and molecular mechanisms of action have not been well established. Here we characterize a new immunophilin ligand that interacts with both FK506 binding protein 12 (FKBP12) and FKBP52, and demonstrate that JNJ460 induces neurite outgrowth from freshly explanted dorsal root ganglia (DRG) in a Schwann cell-dependent manner. Purified cultures of neurons fail to respond to these drugs, but cultures containing Schwann cells and neurons respond with neurite outgrowth, as do neurons grown in conditioned medium from JNJ460-treated Schwann cells. Using microarray analysis and a transcription reporter assay, we show that JNJ460 induces a series of transcriptional changes that occur in a temporal cascade. Among the Schwann cell-expressed genes upregulated following JNJ460 treatment is the POU transcription factor SCIP, which has been shown to regulate Schwann cell gene transcription and differentiation. JNJ460 potentiated transforming growth factor β (TGF-β)-induced transcriptional activation and SCIP induction in Schwann cells, by altering the interaction between FKBP12 and the TGF-β type I receptor, TβR1. Finally, to test whether JNJ460 enhances neurite regeneration in vivo, we treated animals with JNJ460 for 30 days following mechanical transection of the sciatic nerve and demonstrated myelin and axonal hypertrophy at the ultrastructural level. Collectively, these data suggest that Schwann cells play an important role in the biological effects of immunophilin ligands by affecting neuron-glial signaling during regeneration. Summary: The cellular and molecular mechanisms responsible for the regenerative effects of immunophilin ligands are not well understood. Here we show that the neuritogenic effects of JNJ460 in a DRG model depend on interactions between neurons and Schwann cells. Treatment of purified Schwann cells with JNJ460 alters Schwann cell gene expression, and promotes the generation of factors that act on neurons. These data indicate that Schwann cells play an important role in the actions of immunophilin ligands.

Original languageEnglish (US)
Pages (from-to)351-366
Number of pages16
JournalNeuroscience
Volume124
Issue number2
DOIs
StatePublished - 2004

Fingerprint

Schwann Cells
Tacrolimus
Immunophilins
Neurons
Ligands
Tacrolimus Binding Proteins
Spinal Ganglia
Transforming Growth Factors
Regeneration
JNJ460
POU Domain Factors
Growth Factor Receptors
Neurites
Sciatic Nerve
Microarray Analysis
Conditioned Culture Medium
Myelin Sheath
Cell Communication
Neuroglia
Hypertrophy

Keywords

  • FK506 derivatives
  • FKBP52
  • Immunophilin
  • Neural regeneration FKBP12
  • Schwann cells
  • TGF-β

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Birge, R. B., Wadsworth, S., Akakura, R., Abeysinghe, H., Kanojia, R., Macielag, M., ... Weinstein, D. E. (2004). A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive FK506 derivative, JNJ460. Neuroscience, 124(2), 351-366. https://doi.org/10.1016/j.neuroscience.2003.10.013

A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive FK506 derivative, JNJ460. / Birge, R. B.; Wadsworth, S.; Akakura, R.; Abeysinghe, H.; Kanojia, R.; Macielag, M.; Desbarats, J.; Escalante, M.; Singh, K.; Sundarababu, S.; Parris, K.; Childs, Geoffrey J.; August, A.; Siekierka, J.; Weinstein, D. E.

In: Neuroscience, Vol. 124, No. 2, 2004, p. 351-366.

Research output: Contribution to journalArticle

Birge, RB, Wadsworth, S, Akakura, R, Abeysinghe, H, Kanojia, R, Macielag, M, Desbarats, J, Escalante, M, Singh, K, Sundarababu, S, Parris, K, Childs, GJ, August, A, Siekierka, J & Weinstein, DE 2004, 'A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive FK506 derivative, JNJ460', Neuroscience, vol. 124, no. 2, pp. 351-366. https://doi.org/10.1016/j.neuroscience.2003.10.013
Birge, R. B. ; Wadsworth, S. ; Akakura, R. ; Abeysinghe, H. ; Kanojia, R. ; Macielag, M. ; Desbarats, J. ; Escalante, M. ; Singh, K. ; Sundarababu, S. ; Parris, K. ; Childs, Geoffrey J. ; August, A. ; Siekierka, J. ; Weinstein, D. E. / A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive FK506 derivative, JNJ460. In: Neuroscience. 2004 ; Vol. 124, No. 2. pp. 351-366.
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AU - Abeysinghe, H.

AU - Kanojia, R.

AU - Macielag, M.

AU - Desbarats, J.

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AU - Weinstein, D. E.

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