Hydroxycarbamide stimulates the production of proinflammatory cytokines by endothelial cells: relevance to sickle cell disease.
OBJECTIVE
The clinical hallmarks of sickle cell disease (SCD) are vaso-occlusive crises (VOC) triggered by red blood cells (RBC) stiffening and abnormal adhesion to vascular endothelial cells (VEC) in the context of chronic inflammation, cell activation, and vascular tone abnormalities. Hydroxycarbamide (HC) is the only drug with a proven efficacy in decreasing VOC frequency. HC decreases RBC stiffening, modulates adhesion protein expression by RBC and VEC, and reduces endothelin-1 production by VEC. Our objective was to test whether HC could also affect inflammation through its action on VEC.


METHODS
We used microarrays to study the effect of HC on the transcriptome of transformed human bone marrow endothelial cell, a cell line derived from bone marrow microcirculation (the predilection site of VOC), in basal and proinflammatory conditions. Microarray results were confirmed by real-time quantitative PCR and protein analysis on transformed human bone marrow endothelial cell (TrHBMEC) and on two other VEC types in the primary culture: human pulmonary microcirculation endothelial cell (HPMEC) and human umbilical vein endothelial cell (HUVEC a classical model for the macrocirculation).


RESULTS
HC had a significant effect on the expression of genes of the 'inflammation pathway'. Strikingly, it stimulates the expression of proinflammatory genes such as IL1A, IL1B, IL6, IL8, CCL2, CCL5, CCL20, and CCL8 in all the tested VEC types.


CONCLUSIONS
Our study confirms that VECs are significant targets of HC in the context of SCD and identifies its earlier unsuspected action on another major component of SCD pathophysiology, that is, the 'inflammation pathway'.
Laurance
Sandrine
S
INSERM UMR_S 763, Hôpital Robert Debré, 48 boulevard Sérurier, Paris, France.
Pellay
François-Xavier
FX
Dossou-Yovo
Omer P
OP
Verger
Emmanuelle
E
Krishnamoorthy
Rajagopal
R
Lapoumeroulie
Claudine
C
Benecke
Arndt
A
Elion
Jacques
J
D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000986:Antisickling Agents / Q000494:pharmacology*; D002460:Cell Line; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000986:Antisickling Agents; D019742:Chemokines, CC; D016207:Cytokines; D018836:Inflammation Mediators; D007378:Interleukins; D012333:RNA, Messenger; D006918:Hydroxyurea