gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury

Abstract

Adult peripheral neurons, in contrast to adult central neurons, are capable of regeneration after axonal damage. Much attention has focused on the changes that accompany this regeneration in two places, the distal nerve segment (where phagocytosis of axonal debris, changes in the surface properties of Schwann cells, and induction of growth factors and cytokines occur) and the neuronal cell body (where dramatic changes in cell morphology and gene expression occur). The changes in the axotomized cell body are often referred to as the “cell body response.” The focus of the current review is a family of cytokines, the glycoprotein 130 (gp130) cytokines, which produce their actions through a common gp130 signaling receptor and which function as injury signals for axotomized peripheral neurons, triggering changes in gene expression and in neurite outgrowth. These cytokines play important roles in the responses of sympathetic, sensory, and motor neurons to injury. The best studied of these cytokines in this context are leukemia inhibitory factor (LIF) and interleukin (IL)-6, but experiments with conditional gp130 knockout animals suggest that other members of this family, not yet determined, are also involved. The primary gp130 signaling pathway shown to be involved is the activation of Janus kinase (JAK) and the transcription factors Signal Transducers and Activators of Transcription (STAT), though other downstream pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) may also play a role. gp130 signaling may involve paracrine, retrograde, and autocrine actions of these cytokines. Recent studies suggest that manipulation of this cytokine system can also stimulate regeneration by injured central neurons.

Identification of a Novel Neurotrophic Factor from Primary Retinal Müller Cells Using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)

“…Together with other glycoprotein-130-related cytokines, LIF activates the Janus kinase and STAT pathways (48). The capacity of LIF to counteract oxidative stress (29,51) fits well with the described role of transferrin in the retina, and as our study found both proteins at reduced levels in de-differentiated cells concomitant with a loss of survival-prolonging capacities, this suggests an important role of RMGs in buffering oxidative stress in the healthy retina.…”

“…LIF belongs to the IL6 family, also termed glycoprotein 130 cytokines (48). Other members of this cytokine family include ciliary neurotrophic factor, IL11, and oncostatin M, all of which signal through a common glycoprotein 130 receptor (48). LIF exhibits multiple biological effects in the developing vertebrate retina (49) and has been widely investigated as a neurotrophic factor in the retina (14, 50 -52).…”

“…LIF belongs to the IL6 family, also termed glycoprotein 130 cytokines (48). Other members of this cytokine family include ciliary neurotrophic factor, IL11, and oncostatin M, all of which signal through a common glycoprotein 130 receptor (48).…”

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

“…In the brain, LIF is involved in neural stem cell maintenance and axonal growth, and in modulation of gene expression [100]. During embryonic development, LIF is expressed in the olfactory placode, which led to the hypothesis that LIF affects GnRH neuron migration [54].…”

The Pros and Cons of Growth Factors and Cytokines in Peripheral Axon Regeneration

“…They are subgrouped into peptide families according to sequence similarity and homology of receptors to which they bind. Several comprehensive reviews have described the localization, regulation, and function of neurotrophins (NGF, BDNF, NT-3/4/5), glial cellderived neurotrophic factor (GDNF) family members (GDNF, NTN, PSP, ART), fibroblast growth factors (FGF-1, FGF-2), insulin-like growth factors (IGF-I, IGF-II), neuregulins (GGF), neuropeptides (galanin, VIP, PACAP), and neuropoietic cytokines belonging to the gp130 family (CNTF, LIF, CT-1, OSM, IL-6, IL-11) in the lesioned peripheral nervous system (PNS) (Boyd & Gordon, 2003;Fawcett & Keynes, 1990;Fu & Gordon, 1997;Gordon, 2009;Grothe, Haastert, & Jungnickel, 2006;Hökfelt, Zhang, & Wiesenfeld-Hallin, 1994;Klimaschewski, Kummer, & Heym, 1996;Terenghi, 1999;Zigmond, 2012). Here, we focus our discussion on the ability of these molecules to promote neuronal survival and regeneration in the lesioned PNS, with particular emphasis on their role in axonal sprouting.…”