title: Secretory leukocyte protease inhibitor reverses inhibition by CNS myelin, promotes regeneration in the optic nerve, and suppresses expression of the transforming growth factor-β signaling protein Smad2.
abstract: After CNS injury, axonal regeneration is limited by myelin-associated inhibitors; however, this can be overcome through elevation of intracellular cyclic AMP (cAMP), as occurs with conditioning lesions of the sciatic nerve. This study reports that expression of secretory leukocyte protease inhibitor (SLPI) is strongly upregulated in response to elevation of cAMP. We also show that SLPI can overcome inhibition by CNS myelin and significantly enhance regeneration of transected retinal ganglion cell axons in rats. Furthermore, regeneration of dorsal column axons does not occur after a conditioning lesion in SLPI null mutant mice, indicating that expression of SLPI is required for the conditioning lesion effect. Mechanistically, we demonstrate that SLPI localizes to the nuclei of neurons, binds to the Smad2 promoter, and reduces levels of Smad2 protein. Adenoviral overexpression of Smad2 also blocked SLPI-induced axonal regeneration. SLPI and Smad2 may therefore represent new targets for therapeutic intervention in CNS injury.
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA.
authors.forename: Sari S
authors.initials: SS
authors.lastname: Hannila
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Siddiq
authors.forename: Jason B
authors.initials: JB
authors.lastname: Carmel
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hou
authors.forename: Nagarathnamma
authors.initials: N
authors.lastname: Chaudhry
authors.forename: Peter M J
authors.initials: PM
authors.lastname: Bradley
authors.forename: Melissa
authors.initials: M
authors.lastname: Hilaire
authors.forename: Erica L
authors.initials: EL
authors.lastname: Richman
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.forename: Marie T
authors.initials: MT
authors.lastname: Filbin
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D007278:Injections, Spinal; D008297:Male; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology*; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000502:physiology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D034741:RNA, Small Interfering; D053481:Secretory Leukocyte Peptidase Inhibitor; C506816:Slpi protein, rat; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D000242:Cyclic AMP