Proapoptotic effect of curcumin on human neutrophils: activation of the p38 mitogen-activated protein kinase pathway.
OBJECTIVE
Despite advances in the management of sepsis and acute respiratory distress syndrome, the mortality rate remains high. Delayed apoptosis of neutrophils is associated with multiple organ failure under those conditions. Thus, development of nontoxic neutrophil apoptosis regulating molecules may provide a novel therapeutic strategy. Curcumin is a promising dietary supplement for cancer prevention. However, the effect of curcumin on human neutrophil apoptosis remains unknown. We therefore hypothesized that curcumin would produce a proapoptotic effect on neutrophils.


METHODS
Prospective, controlled, and randomized in vitro study.


METHODS
Research institute laboratory.


METHODS
Human peripheral neutrophils obtained from normal subjects.


METHODS
None.


RESULTS
In the presence or absence of curcumin, both spontaneous neutrophil apoptosis and apoptosis of neutrophils following transmigration across a human lung endothelium-epithelium bilayer were studied by morphology and terminal dUTP nucleotide end labeling analyses, respectively. Myeloperoxidase activity and migration assays were performed to determine the impact of curcumin on neutrophil function. To elucidate the potential mechanism, the p38 mitogen-activated protein kinase pathway and caspase-3 activity were examined by Western blotting and enzymatic analyses. The data demonstrate that curcumin increased constitutive neutrophil apoptosis and abrogated the transbilayer migration-induced delay in neutrophil apoptosis. Neutrophil activation was reduced by curcumin treatment as evidenced by a decrease in migration and myeloperoxidase release. A marked increase in p38 phosphorylation and caspase-3 activity was observed following curcumin exposure. In addition, inhibition of p38 mitogen-activated protein kinase with SB203580 suppressed apoptosis and caspase-3 activation induced by curcumin. Thus, activation of p38 mitogen-activated protein kinase or an increase in caspase-3 activity appears to contribute to the proapoptotic effect of human neutrophil apoptosis by curcumin.


CONCLUSIONS
The characteristics of curcumin, including its proapoptotic effect and antidegranulation effect, make it a potential candidate for the therapy of neutrophil-induced lung injury and sepsis.
Hu
Maowen
M
Division of Surgical Research, North Shore University Hospital and Long Island Jewish (LIJ) Medical Center, Manhasset, NY 11030, USA.
Du
Qiaoting
Q
Vancurova
Ivana
I
Lin
Xinchun
X
Miller
Edmund J
EJ
Simms
H Hank
HH
Wang
Ping
P
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D018805:Sepsis / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D048051:p38 Mitogen-Activated Protein Kinases; D003474:Curcumin