Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury

Abstract

Oligodendrocytes (OLs) and their myelin membranes are the apparent injury targets in the putative human autoimmune disease multiple sclerosis. The basis for this selective injury remains to be defined. OLs in vitro have been shown to be susceptible to both tumor necrosis factor (TNF) and non‐TNF‐dependent immune effector mechanisms. The former involves initial nuclear injury (apoptosis); the latter, when mediated by activated T cells, involves initial cell membrane injury (lysis). In the current study, we determined whether human adult CNS‐derived OLs could be protected from the above immune effector mechanisms by selected neurotrophic factors (CNTF, BDNF, NGF, NT‐3, and NT‐4/5) or cytokines demonstrated to protect from human or experimental autoimmune demyelinating diseases (β‐interferon [IFN], IL‐10, and TGF‐β). Nuclear injury was assessed in terms of DNA fragmentation using a DNA nick‐end‐labelling technique; cell membrane injury was assessed by lactate dehydrogenase or chromium 51 release. MTT and cell counting assays were used to assess cell viability and cell loss, respectively. Amongst the neurotrophic factors and cytokines tested, only CNTF significantly protected the OLs from TNF‐mediated injury. CNTF also protected the OLs from serum deprivation‐induced apoptosis. CNTF, however, did not protect the OLs from injury induced by activated CD4+ T cells. CNTF also did not protect human fetal cortical neurons from serum deprivation or TNF‐induced DNA fragmentation, nor did it protect the U251 human glioma cell line from DNA fragmentation induced by a combination of TNF and reduced serum concentration in the culture media. Our results indicate that potential protective effects of neurotrophic factors or cytokines on neural cell populations can be selective both for cell type involved and mechanism of immune‐mediated injury. CNTF is the protective factor selective for nuclear‐directed injury of OLs. © 1996 Wiley‐Liss, Inc.

Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis

“…In vitro CNTF promotes the survival of neurons 20,58 and reduces tumor necrosis factor-␣ and serum deprivationinduced cell death of oligodendrocytes. 19,59,60 In vivo, it prevents the degeneration of axotomized neurons. 23 In CNTF-deficient mice induction of EAE with MOG peptide results in more severe axonal damage, increased number of apoptotic oligodendrocytes, and a reduction in proliferating oligodendrocyte progenitor cells compared to WT mice.…”

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

“…The presence of inflammatory cytokines can be important in influencing CNS regeneration, either by direct neurotrophic actions, by causing astrocytes to become reactive, and /or by affecting the neurotrophic activity of astrocytes. It is possible that under certain conditions, inflammatory cytokines become impairments to the recovery of the CNS; for instance, TNF-␣ can be toxic to oligodendrocytes (Louis et al, 1993;D'Souza et al, 1996). Understanding and regulating the activities of inflammatory cytokines within the CNS constitutes a key step toward effecting CNS recovery.…”

Central Nervous System-Initiated Inflammation and Neurotrophism in Trauma: IL-1β Is Required for the Production of Ciliary Neurotrophic Factor

“…15 and 41). A number of studies have observed that TNF-␣ produces apoptotic death to oligodendrocytes and neurons (19,21), and some reports have also implicated IL-1␤ in the mediation of neuronal death, particularly following ischemic and excitotoxic brain injury (42)(43)(44). Inflammation following CNS trauma would therefore be detrimental in the context of potential injury to neurons and oligodendrocytes, and reports of the correspondence of the number of macrophages/microglia with the amount of tissue damage at each level of the spinal cord in contusion injury (e.g., Carlson et al (45)) would be consistent with such a hypothesis.…”

“…18). CNTF has been shown to be an important maturation factor for oligodendrocytes, to promote their synthesis of myelin proteins (19,20), and to protect oligodendrocytes from apoptotic death induced by several agents (19,21). Thus, the regulation of CNTF expression in the CNS following injury may be particularly important for attenuating neuronal and oligodendrocyte death.…”