Cytokines that promote nerve regeneration.

Afteraxonaldamage,regenerationoccursspontaneouslyinthemam-malianperipheralnervoussystem(PNS);however,thisisextremelyrarein the central nervous system (CNS). Nerve regeneration is generallythought to depend on two types of factors: intrinsic and extrinsic(Bosse, 2012; Ferguson and Son, 2011 ). The study of the extrinsic factorsthatlimitCNSregenerationhasalonghistory( CaroniandSchwab,1988;Galtrey and Fawcett, 2007; Lee and Zheng, 2012 ); however, the study onwhat regulates the intrinsic growth c apacity of central neurons has re-ceivedattentionmuchmorerecently( Liuetal.,2011).Partoftheintrinsicmechanism has long been believed to involve changes in gene transcrip-tion, a part of a set of changes referred to as the “cell body response”(Grafstein, 1975; Skene and Willard, 1981b; Smith and Skene, 1997;Watson, 1974) and triggered either by factors induced by axotomy orby target derived factors whose in ﬂuence is removed by axotomy or byboth (Cragg, 1970; Zigmond, 2012).Inarecentpaperentitled “IL-6promotesregenerationandfunctionalrecovery after cortical spinal tract injury by reactivating intrinsic growthprogram of neurons and enhancing synapse formation ”, Yang et al.(2012) reported that infusion of the cytokine interleukin (IL)-6 into thespinal cord at the time of a dorsal he misection promoted regenerationandfunctionalrecoveryof thecorticospinaltract(CST),anervepathwayconsidered to have a particularly low intrinsic growth capacity(Blackmore et al., 2012; Liu et al., 2010 ). IL-6 is a member of a family ofcytokinesreferredtoastheglycoprotein(gp)130familyortheIL-6fam-ily(Bazan,1991).The ﬁrstofthesenamescomesfromthefactthatthesecytokines act on a set of heteromeric receptors all of which contain thesignalingsubunitgp130 ( Taga,1996).Activationofgp130leads to phos-phorylation of the transcription factor signal transducer and activator oftranscription 3 (STAT3) by the enzyme Janus kinase (JAK), dimerizationof the factor and its translocation to the cell nucleus, and activation of aset of responsive genes ( Heinrich et al., 2003). In addition, gp130 cantrigger other signaling pathways including the mitogen-activated pro-tein kinase/extracellular signal-regulated kinase (ERK) pathway ( Ernstand Jenkins, 2004). These cytokines are pleiotropic and produce manyoverlapping effects in the nervous system and elsewhere. Several ofthem, including IL-6, are induced in the nervous system after injury(Banner and Patterson, 1994; Bolin et al., 1995; Kiefer et al., 1993;Murphy et al., 1995; Sun et al., 1994 ).Discovery that exogenous gp130 cytokine actions are involved inPNS developmentIt is striking that the earliest evidence establishing neurons as targetsfor gp130 cytokines both involved the peripheral sympathetic nervoussystem and examples of neurotransmitter plasticity, one occurring innormal neonatal development and the other occurring in adult neuronsafter injury (Landis, 1996; Zigmond et al., 1996). The ﬁrst of these wasdiscovered serendipitously in studies on neonatal neurons from the su-perior cervical ganglion (SCG) that were co-cultured with heart cells orin heart cell conditioned medium. These studies revealed surprisinglythat, while the neurons initially released norepinephrine and formednoradrenergic synapses as expected, with time they began to releaseacetylcholine and to communicate with their target cells via muscarinicreceptors (Furshpan et al., 1976). The biological activity in the condi-tioned medium that triggered this change was referred to as the cholin-ergic differentiation factor (CDF), and the phenomenon was referred toas “the cholinergic switch”. A very similar phenomenon was latershowntooccurinvivoduringthe ﬁrst2–3 weeksoflifeinrestrictedsub-populations of sympathetic neurons, namely those innervating sweatglands (Schotzinger and Landis, 1988, 1990) and the periosteum, theconnective tissue that surrounds bone ( Asmus et al., 2000, 2001).Yamamorietal. (1989)isolatedtheCDF fromheart cell conditionedmediumandidentiﬁeditasleukemiainhibitoryfactor(LIF),which,likeIL-6,isagp130cytokine.Theypointedout,however,thattheroleofthismolecule in normal development was unknown. Nevertheless, it stillcame as a surprise when later the cholinergic switch was shown tooccur normally in animals in which the gene for LIF had been knockedout (Rao et al., 1993). In line with that ﬁnding, it turns out that LIF isnot actually expressed bythe exocrine cells in the sweat gland, the tar-getsofthecholinergicsympatheticinnervation(Raoetal.,1993;Stanke