title: Rescue of TNFalpha-inhibited neuronal cells by IGF-1 involves Akt and c-Jun N-terminal kinases.
abstract: Proinflammatory cytokines, especially tumor necrosis factor alpha (TNFalpha), is a pleiotropic mediator of a diverse array of physiologic and neurologic functions and is upregulated during various inflammatory and neurodegenerative diseases. A common survival response during such situations is the increased expression of the hormone insulin-like growth factor 1 (IGF-1). Although it was thought previously that the mechanisms of TNFalpha and IGF-1 action were unrelated, it has been shown that low doses of TNFalpha can inhibit the survival effects of IGF-1 in mouse cerebellar granule neurons. We used a neuronal cell line SH-SY5Y, which underwent apoptosis in response to TNFalpha and this process could be reversed substantially by IGF-1. Crosstalk between signaling pathways of these two factors was found at various points downstream of their signal transduction. To determine the mechanisms of IGF-1-mediated rescue, we looked at the MAP kinases, which are known to be involved in IGF-1 as well as TNFalpha signaling. The c-Jun N-terminal kinase pathway, which is known normally to promote cell death, was found to actually promote survival of TNFalpha-mediated cell death. Inhibiting the c-Jun survival pathway completely reversed the rescue mediated by IGF-1. In addition, the Akt pathway played an equally important role in this rescue.
authors.affiliation: National Institute Of Immunology, New Delhi, India.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Kenchappa
authors.forename: Ajay
authors.initials: A
authors.lastname: Yadav
authors.forename: Gurvinder
authors.initials: G
authors.lastname: Singh
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nandana
authors.forename: Kakoli
authors.initials: K
authors.lastname: Banerjee
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D002867:Chromones; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009025:Morpholines; D009842:Oligopeptides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002083:Butylated Hydroxyanisole; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D001728:Dicumarol; C056289:GSK peptide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases