Platelets and megakaryocytes contain functional nuclear factor-kappaB.
OBJECTIVE
To investigate the presence and role of NF-kappaB proteins in megakaryocytes and platelets. The nuclear factor-kappaB (NF-kappaB) transcription factor family is well known for its role in eliciting inflammation and promoting cell survival. We discovered that human megakaryocytes and platelets express the majority of NF-kappaB family members, including the regulatory inhibitor-kappaB (I-kappaB) and I-kappa kinase (IKK) molecules.


RESULTS
Anucleate platelets exposed to NF-kappaB inhibitors demonstrated impaired fundamental functions involved in repairing vascular injury and thrombus formation. Specifically, NF-kappaB inhibition diminished lamellapodia formation, decreased clot retraction times, and reduced thrombus stability. Moreover, inhibition of I-kappaB-alpha phosphorylation (BAY-11-7082) reverted fully spread platelets back to a spheroid morphology. Addition of recombinant IKK-beta or I-kappaB-alpha protein to BAY inhibitor-treated platelets partially restored platelet spreading in I-kappaB-alpha inhibited platelets, and addition of active IKK-beta increased endogenous I-kappaB-alpha phosphorylation levels.


CONCLUSIONS
These novel findings support a crucial and nonclassical role for the NF-kappaB family in modulating platelet function and reveal that platelets are sensitive to NF-kappaB inhibitors. As NF-kappaB inhibitors are being developed as antiinflammatory and anticancer agents, they may have unintended effects on platelets. On the basis of these data, NF-kappaB is also identified as a new target to dampen unwanted platelet activation.
Spinelli
Sherry L
SL
Department of Environmental Medicine, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Casey
Ann E
AE
Pollock
Stephen J
SJ
Gertz
Jacqueline M
JM
McMillan
David H
DH
Narasipura
Srinivasa D
SD
Mody
Nipa A
NA
King
Michael R
MR
Maggirwar
Sanjay B
SB
Francis
Charles W
CW
Taubman
Mark B
MB
Blumberg
Neil
N
Phipps
Richard P
RP
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; D013450:Sulfones; D051996:Transcription Factor RelA