Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex.
Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immunoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immunoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death.
Maldonado
Michelle
M
PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Baybis
Marianna
M
Newman
David
D
Kolson
Dennis L
DL
Chen
Wei
W
McKhann
Guy
G
Gutmann
David H
DH
Crino
Peter B
PB
D000328:Adult; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins
D016328:NF-kappa B; D011506:Proteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases