title: Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina.
abstract: Injured adult retinal ganglion cells (RGCs) regrow axons into peripheral nerve (PN) grafted onto cut optic nerve. Survival and regeneration of RGCs is increased by intraocular injections of ciliary neurotrophic factor (CNTF) and axonal regeneration is further enhanced by co-injection of a cyclic AMP analogue (CPT-cAMP). Based on these data, and because cytokine signaling is negatively regulated by suppressor of cytokine signaling (SOCS) proteins, we set out to determine whether CNTF injections increase retinal SOCS expression and whether any changes are attenuated by co-injection with CPT-cAMP. Using quantitative PCR we found increased SOCS1, SOCS2 and SOCS3 mRNA levels at various times after a single CNTF injection. Expression remained high for many days. SOCS protein levels were also increased. In situ hybridization revealed that RGCs express SOCS3 mRNA, and SOCS expression in cultured RGCs was increased by CNTF. Co-injection of CPT-cAMP reduced CNTF induced expression of SOCS1 and SOCS3 mRNA and decreased SOCS3 protein expression. CNTF injection also transiently increased retinal leukemia inhibitory factor (LIF) expression, an effect that was also moderated by CPT-cAMP. We propose that, along with known reparative effects of elevated cAMP on neurons, reducing SOCS upregulation may be an additional way in which cyclic nucleotides augment cytokine-induced regenerative responses in the injured CNS.
authors.affiliation: School of Anatomy and Human Biology M309, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Park
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Jillian
authors.initials: J
authors.lastname: Muhling
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pollett
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dallimore
authors.forename: Ann M
authors.initials: AM
authors.lastname: Turnley
authors.forename: Qi
authors.initials: Q
authors.lastname: Cui
authors.forename: Alan R
authors.initials: AR
authors.lastname: Harvey
mesh_terms: D000818:Animals; D001369:Axons / Q000637:transplantation; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D000242:Cyclic AMP / Q000008:administration & dosage / Q000031:analogs & derivatives; D016207:Cytokines / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration / Q000187:drug effects*; D012160:Retina / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics; D019737:Transplants
chemical_list: D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D000242:Cyclic AMP