NEUROTROPHINS AND THEIR RECEPTORS IN NERVE INJURY AND REPAIR

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the i mmune system and inflammatory responses. The cytokine families include , but are not limited to, interleukins (IL-I alpha, IL-I beta, ILIra a nd IL-2-IL-15), chemokines (IL-8/NAP-I, NAP-2, MIP-I alpha and beta, M CAF/MCP-I, MGSA and RANTES), tumor necrosis factors (TNF-alpha and TNF -beta), interferons (INF-alpha, beta and gamma), colony stimulating fa ctors (G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs), growth f actors (EGF, FGF, PDGF, TGF alpha, TGF beta and ECGF), neuropoietins ( LIF, CNTF, OM and IL-6), and neurotrophins (BDNF, NGF. NT-3-NT-6 and G DNF). The neurotrophins represent a family of survival and differentia tion factors that exert profound effects in the central and peripheral nervous system (PNS). The neurotrophins are currently under investiga tion as therapeutic agents for the treatment of neurodegenerative diso rders and nerve injury either individually or in combination with othe r trophic factors such as ciliary neurotrophic factor (CNTF) or fibrob last growth factor (FGF). Responsiveness of neurons to a given neurotr ophin is governed by the expression of two classes of cell surface rec eptor. For nerve growth factor (NGF), these are p75(NTR) (p75) and p14 0(trk) (referred to as trk or trkA), which binds both BDNF and neurotr ophin (NT)-4/5, and trkC receptor, which binds only NT-3. After bindin g ligand, the neurotrophin-receptor complex is internalized and retrog radely transported in the axon to the soma. Both receptors undergo lig and-induced dimerization, which activates multiple signal transduction pathways. These include the ras-dependent pathway utilized by trk to mediate neurotrophin effects such as survival and differentiation. Ind eed, cellular diversity in the nervous system evolves from the concert ed processes of cell proliferation, differentiation, migration, surviv al, and synapse formation. Neural adhesion and extracellular matrix mo lecules have been shown to play crucial roles in axonal migration, gui dance, and growth cone targeting. Proinflammatory cytokines, released by activated macrophages and monocytes during infection, can act on ne ural targets that control thermogenesis, behavior, and mood. In additi on to induction of fever, cytokines induce other biological functions associated with the acute phase response, including hypophagia and sle ep. Cytokine production has been detected within the central nervous s ystem as a result of brain injury, following stab wound to the brain, during viral and bacterial infections (AIDS and meningitis), and in ne urodegenerative processes (multiple sclerosis and Alzheimer's disease) . Novel cytokine therapies, such as anticytokine antibodies or specifi c receptor antagonists acting on the cytokine network may provide an o ptimistic feature for treatment of multiple sclerosis and other diseas es in which cytokines have been implicated. (C) 1997 Elsevier Science Ltd.