TY - JOUR
T1 - Activation of NF-κB and c-jun transcription factors in multiple sclerosis lesions
T2 - Implications for oligodendrocyte pathology
AU - Bonetti, Bruno
AU - Stegagno, Chiara
AU - Cannella, Barbara
AU - Rizzuto, Nicola
AU - Moretto, Giuseppe
AU - Raine, Cedric S.
N1 - Funding Information:
Supported in part by the Fondazione Italiana Sclerosi Multipla ( 97/R/17 ) to B.B., and the following to C.S.R.: NS 08952 and NS 11920 from the NINDS; NMSS RG 1001-I-9 from the National Multiple Sclerosis Society; the Sol Goldman Charitable Trust; and the Wollowick Family Foundation.
PY - 1999/11
Y1 - 1999/11
N2 - Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-α, are known to generate survival signals through the activation of the transcription factors NF-κB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-κB complex and its inhibitor, IκB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-κB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IκB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.
AB - Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-α, are known to generate survival signals through the activation of the transcription factors NF-κB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-κB complex and its inhibitor, IκB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-κB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IκB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.
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U2 - 10.1016/S0002-9440(10)65456-9
DO - 10.1016/S0002-9440(10)65456-9
M3 - Article
C2 - 10550297
AN - SCOPUS:0032589563
SN - 0002-9440
VL - 155
SP - 1433
EP - 1438
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -