Abstract
Interleukin-1α (IL-1α) stimulates a disintegrin and metalloproteinase, ADAM-17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPα) in human primary astrocytes. To characterize the mechanism by which IL-1α promotes the non-amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL-1α significantly increased levels of ADAM-10 and ADAM-17 mRNA in 16 hr. Upregulation of ADAM-17 mRNA by IL-1α was more pronounced despite higher basal levels of ADAM-10 mRNA. This pattern was also observed at the protein level with the upregulation of α-secretase. RNA interference (RNAi) of ADAM-10 and ADAM-17 inhibited IL-1α-stimulated sAPPα release and the effect was more pronounced with ADAM-17 RNAi. Concomitantly, the level of sAPPα was significantly increased by IL-1α in 48 hr; however, IL-1α stimulated cell-associated APP levels maximally at 6 h but the induction declined at 48 hr. IL-1α treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid-β, Aβ-40, and Aβ-42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL-1α-stimulated α-secretase activity and sAPPα release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL-1α and blocking this pathway attenuated activation of IL-1α-induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPα regulation by IL-1α that involves ADAM-10, ADAM-17 and p38 MAPK upstream of MEK and PI3K.
| Original language | English |
|---|---|
| Pages (from-to) | 106-118 |
| Number of pages | 13 |
| Journal | Journal of Neuroscience Research |
| Volume | 84 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2006 |
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Keywords
- Alzheimer's disease
- Inflammation
- MAP kinase
- Matrix metalloproteinase
- RNA interference
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Interleukin-1α stimulates non-amyloidogenic pathway by α-secretase (ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase. / Bandyopadhyay, Sanghamitra; Hartley, Dean M.; Cahill, Catherine M.; Lahiri, Debomoy; Chattopadhyay, Naibedya; Rogers, Jack T.
In: Journal of Neuroscience Research, Vol. 84, No. 1, 07.2006, p. 106-118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interleukin-1α stimulates non-amyloidogenic pathway by α-secretase (ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase
AU - Bandyopadhyay, Sanghamitra
AU - Hartley, Dean M.
AU - Cahill, Catherine M.
AU - Lahiri, Debomoy
AU - Chattopadhyay, Naibedya
AU - Rogers, Jack T.
PY - 2006/7
Y1 - 2006/7
N2 - Interleukin-1α (IL-1α) stimulates a disintegrin and metalloproteinase, ADAM-17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPα) in human primary astrocytes. To characterize the mechanism by which IL-1α promotes the non-amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL-1α significantly increased levels of ADAM-10 and ADAM-17 mRNA in 16 hr. Upregulation of ADAM-17 mRNA by IL-1α was more pronounced despite higher basal levels of ADAM-10 mRNA. This pattern was also observed at the protein level with the upregulation of α-secretase. RNA interference (RNAi) of ADAM-10 and ADAM-17 inhibited IL-1α-stimulated sAPPα release and the effect was more pronounced with ADAM-17 RNAi. Concomitantly, the level of sAPPα was significantly increased by IL-1α in 48 hr; however, IL-1α stimulated cell-associated APP levels maximally at 6 h but the induction declined at 48 hr. IL-1α treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid-β, Aβ-40, and Aβ-42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL-1α-stimulated α-secretase activity and sAPPα release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL-1α and blocking this pathway attenuated activation of IL-1α-induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPα regulation by IL-1α that involves ADAM-10, ADAM-17 and p38 MAPK upstream of MEK and PI3K.
AB - Interleukin-1α (IL-1α) stimulates a disintegrin and metalloproteinase, ADAM-17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPα) in human primary astrocytes. To characterize the mechanism by which IL-1α promotes the non-amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL-1α significantly increased levels of ADAM-10 and ADAM-17 mRNA in 16 hr. Upregulation of ADAM-17 mRNA by IL-1α was more pronounced despite higher basal levels of ADAM-10 mRNA. This pattern was also observed at the protein level with the upregulation of α-secretase. RNA interference (RNAi) of ADAM-10 and ADAM-17 inhibited IL-1α-stimulated sAPPα release and the effect was more pronounced with ADAM-17 RNAi. Concomitantly, the level of sAPPα was significantly increased by IL-1α in 48 hr; however, IL-1α stimulated cell-associated APP levels maximally at 6 h but the induction declined at 48 hr. IL-1α treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid-β, Aβ-40, and Aβ-42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL-1α-stimulated α-secretase activity and sAPPα release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL-1α and blocking this pathway attenuated activation of IL-1α-induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPα regulation by IL-1α that involves ADAM-10, ADAM-17 and p38 MAPK upstream of MEK and PI3K.
KW - Alzheimer's disease
KW - Inflammation
KW - MAP kinase
KW - Matrix metalloproteinase
KW - RNA interference
UR - http://www.scopus.com/inward/record.url?scp=33745793612&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745793612&partnerID=8YFLogxK
U2 - 10.1002/jnr.20864
DO - 10.1002/jnr.20864
M3 - Article
VL - 84
SP - 106
EP - 118
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 1
ER -