Tumor necrosis factor(alpha) and insulin-like growth factor-I in the brain: is the whole greater than the sum of its parts?

The cytokine tumor necrosis factor(alpha) (TNFalpha) and the hormone insulin-like growth factor-I (IGF-I) have both been shown to regulate inflammatory events in the central nervous system (CNS). This review summarizes the seemingly independent roles of TNFalpha and IGF-I in promoting and inhibiting neurodegenerative diseases. We then offer evidence that the combined effects of IGF-I and TNFalpha on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo. We propose the framework of a molecular model of hormone-cytokine receptor cross talk in which disparate cell surface receptors share intracellular substrates that regulate neuronal survival.

A new concept in neurodegeneration: TNFalpha is a silencer of survival signals.

The p55 receptor for the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is best characterized by its ability to induce signals that trigger cell death. However, this is not the only way in which this TNF receptor kills neurons. A new view of neurodegeneration has recently emerged in which a TNF receptor induces death through the 'silencing of survival signals' (SOSS), such as phosphatidylinositol 3' kinase (PI3 kinase), that are activated by the insulin-like growth factor 1 receptor. This mechanism of intracellular crosstalk is the most pathophysiologically relevant action of TNFalpha in the brain and is applicable to a broad number of receptors that are localized on the same cell. Treatment of the more-devastating and costly neurodegenerative diseases of our time might be best promoted by increasing the efficacy of neuronal survival factors using new approaches aimed at inhibiting the SOSS.

Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor.

Within the central nervous system, the proinflammatory cytokine tumor necrosis factor (TNF)-alpha is best characterized by its ability to directly foment signals of death. However, recent evidence suggests that TNF-alpha also promotes neurodegeneration through inhibition of a vital survival signal, insulin-like growth factor-I (IGF-I). By inhibiting essential components of the IGF-I survival response, such as phosphatidylinositol 3'-kinase (PI 3-kinase), low nontoxic concentrations of TNF-alpha indirectly trigger the death of neurons. We suggest that this inhibition of survival signaling is a pathophysiologically relevant action of TNF-alpha in the brain. This type of cross-talk by which vastly different receptors utilize shared intracellular substrates is potentially applicable to a broad number of receptors that are coexpressed on the same cell. The use of neuronal growth factors in the treatment of neurodegenerative diseases, such as cerebral ischemia and the AIDS dementia complex, may prove much more effective if the elevated expression of TNF-alpha in these disorders is neutralized.

A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide.

Heightened expression of both a proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and a survival peptide, insulin-like growth factor I (IGF-I), occurs in diverse diseases of the central nervous system, including Alzheimer's disease, multiple sclerosis, the AIDS-dementia complex, and cerebral ischemia. Conventional roles for these two proteins are neuroprotection by IGF-I and neurotoxicity by TNF-alpha. Although the mechanisms of action for IGF-I and TNF-alpha in the central nervous system originally were established as disparate and unrelated, we hypothesized that the signaling pathways of these two cytokines may interact during neurodegeneration. Here we show that concentrations of TNF-alpha as low as 10 pg/ml markedly reduce the capacity of IGF-I to promote survival of primary murine cerebellar granule neurons. TNF-alpha suppresses IGF-I-induced tyrosine phosphorylation of insulin receptor substrate 2 (IRS-2) and inhibits IRS-2-precipitable phosphatidylinositol 3'-kinase activity. These experiments indicate that TNF-alpha promotes IGF-I receptor resistance in neurons and inhibits the ability of the IGF-I receptor to tyrosine-phosphorylate the IRS-2 docking molecule and to subsequently activate the critical downstream enzyme phosphatidylinositol 3'-kinase. This intracellular crosstalk between discrete cytokine receptors reveals a novel pathway that leads to neuronal degeneration whereby a proinflammatory cytokine inhibits receptor signaling by a survival peptide.

Inhibition of antagonist and agonist binding to the human brain muscarinic receptor by arachidonic acid.

Arachidonic acid (AA) inhibits the binding of [3H]quinclidinyl benzilate ([3H]QNB) to the human brain muscarinic cholinergic receptor (mAChR). AA inhibits at lower concentrations in the absence of glutathione (I50 = 15 microM) than in the presence of glutathione (I50 = 42 microM). Inhibition of mAChR binding shows specificity for AA and is reduced with loss of one or more double bonds or with either a decrease or increase in the length of the fatty acid chain. Metabolism of AA by the lipoxygenase, epoxygenase, or fatty acid cyclooxygenase pathways is not required for the inhibitory activity of AA on mAChR binding. Inhibition of [3H]QNB binding by AA is reversible. While decreasing Bmax, AA increased the apparent KD for [3H]QNB and for the more polar antagonist [3H]NMS. In addition, AA inhibits binding of the agonist [3H]oxotremorine-M (I50 = 60 microM) and is the first mediator of mAChR action to be shown to reversibly inhibit mAChR binding. The feedback inhibition of the mAChR by AA may serve a homeostatic function similar to the reuptake and hydrolysis of acetylcholine following cholinergic nerve transmission.

Heme from Alzheimer's brain inhibits muscarinic receptor binding via thiyl radical generation.

An endogenous inhibitor (< 3500 Da) of antagonist binding to the muscarinic acetylcholine receptor (mAChR) has been reported to be elevated 3-fold in Alzheimer's disease (AD) brain. This endogenous inhibitor was found to require the presence of reducing agents such as reduced glutathione (GSH) for optimal activity. In the presence of GSH, the inhibitor was shown to generate thiyl radicals which irreversibly inhibited the mAChR. We now report that the inhibitor contains free heme, a well-established source of oxidative stress capable of generating free radicals and causing neurotoxicity. While FeSO4, microperoxidase and hemin all inhibited antagonist binding to the mAChR, only hemin shared the inhibitor's requirement for GSH. Both the free radical scavengers Trolox and Mn2+, and the metal chelator, EDTA, blocked the activity of the endogenous AD inhibitor and of hemin. Heme oxygenase-1 (HO-1) markedly reduced the activity of both the endogenous AD inhibitor and hemin, indicating that the endogenous inhibitor contains heme. Mass spectrometric analysis confirmed the presence of free heme and heme fragments in fractions of the endogenous AD inhibitor. The antioxidants estrogen, vitamin E and vitamin C all protected the mAChR from irreversible inhibition by the endogenous inhibitor or hemin. These antioxidants may function to protect the integrity of the mAChR in vivo and may have therapeutic potential in AD where free heme could be a source of oxidative stress.