Retinoic acid-induced CD38 antigen promotes leukemia cells attachment and interferon-γ/interleukin-1β-dependent apoptosis of endothelial cells: Implications in the etiology of retinoic acid syndrome

2007 ◽  
Vol 31 (4) ◽  
pp. 455-463 ◽  
Author(s):  
Yin Gao ◽  
Luis H. Camacho ◽  
Kapil Mehta
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Interferon Γ ◽  
Interleukin 1Β ◽  
Leukemia Cells ◽  
Cd38 Antigen ◽  
Retinoic Acid Syndrome

Kininase I-type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin B1receptor agonists

2003 ◽  
Vol 284 (6) ◽  
pp. H1959-H1968 ◽  
Author(s):  
Sakonwun Sangsree ◽  
Viktor Brovkovych ◽  
Richard D. Minshall ◽  
Randal A. Skidgel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Interferon Γ ◽  
Linear Increase ◽  
Interleukin 1Β ◽  
No Production ◽  
Fourfold Increase ◽  
Receptor Agonists ◽  
Inflammatory Conditions ◽  
Golgi Region

Kininase I-type carboxypeptidases convert native kinin agonists for B2receptors into B1receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity. Nitric oxide (NO) release from human lung microvascular endothelial cells (HLMVEC) was measured directly in real time with a porphyrinic microsensor. Bradykinin (1–100 nM) elicited a transient (5 min) peak of generation of NO that was blocked by the B2antagonist HOE 140, whereas B1agonist des-Arg10-kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml interleukin-1β and 200 U/ml interferon-γ for 16 h upregulated B1receptors as shown by an approximately fourfold increase in prolonged (>20 min) output of NO in response to des-Arg10-kallidin, which was blocked by the B1antagonist des-Arg10-Leu9-kallidin. B2receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B1antagonist or carboxypeptidase inhibitor, and completely abolished with a combination of B1and B2receptor antagonists. Furthermore, CPM and CPD activities were increased about twofold in membrane fractions of HLMVEC treated with interleukin-1β and interferon-γ compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show that cellular kininase I-type carboxypeptidases can enhance kinin signaling and NO production by converting B2agonists to B1agonists, especially in inflammatory conditions.

Interferon-γ Induces Retinoic Acid–Inducible Gene-I in Endothelial Cells

Endothelium ◽  
2004 ◽  
Vol 11 (3-4) ◽  
pp. 169-173 ◽  
Author(s):  
T. Imaizumi ◽  
M. Hatakeyama ◽  
K. Yamashita ◽  
H. Yoshida ◽  
A. Ishikawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Interferon Γ ◽  
Inducible Gene

scholarly journals Anticoagulant Effects of Synthetic Retinoids Mediated Via Different Receptors on Human Leukemia and Umbilical Vein Endothelial Cells

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1545-1551 ◽  
Author(s):  
Misako Shibakura ◽  
Takatoshi Koyama ◽  
Takako Saito ◽  
Koichi Shudo ◽  
Nobuyuki Miyasaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Umbilical Vein ◽  
Anticoagulant Effect ◽  
Leukemia Cells ◽  
Receptor Subtypes ◽  
Human Leukemia ◽  
U937 Cells ◽  
Nb4 Cells ◽  
Umbilical Vein Endothelial Cells

AbstractWe recently found that retinoic acids (RAs) exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF ) expression in acute promyelocytic leukemia (APL) cells and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. In the present study, we have used several synthetic retinoids to determine which receptor subtypes are involved in the regulation of TM and TF expression in NB4 APL cells, U937 monoblastic leukemia cells, and human umbilical vein endothelial cells (HUVECs). Am80, which has no binding affinity for RARγ, and Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), upregulated TM and downregulated TF in NB4 and U937 cells, similar to all-trans RA (ATRA). A specific RARα antagonist, Ro41-5253, significantly suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells, and HUVECs. In contrast, only with preincubation with both RARα and RARβ antagonists was downregulation of TF by retinoids suppressed in NB4 cells. These findings indicate that the mechanism of transactivation and transrepression functions of RARs are distinct and also elucidate the major role of RARα in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperation of RARα and RARβ in TF downregulation by retinoids. They also indicate that binding to CRABP is not required for the anticoagulant effect of retinoids and that synthetic retinoids will prove very useful in controlling distinct targets, the TM and TF genes, at the level of transcription, and will permit the development of retinoids with a new type of anticoagulant effect.

Implications of RA-Induced CD38 Antigne in IFN gamma and IL-1 beta Induced Apoptosis of Endothelial Cells and Development of Retinoic Acid Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2217-2217
Author(s):  
Yin Gao ◽  
Kapil Mehta
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Fatal Outcome ◽  
Human Umbilical Cord ◽  
Major Advance ◽  
Gene Expressions ◽  
Ifn Gamma ◽  
Cd38 Expression ◽  
Retinoic Acid Syndrome

Abstract Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid (RA) represents a major advance in the treatment of myeloid leukemia. Despite high remission rates, treatment with RA is associated with the development of a unique constellation of syndromes collectively referred to as ’retinoic acid syndrome’ (RAS). RAS is characterized by fever, dyspnea, weight gain, pulmonary edema, pulmonary infiltrates, pleural and pericardial effusions, episodic hypotension, and acute renal failure, which often lead to a fatal outcome if left uncontrolled. The molecular mechanisms underlying the development of RAS, particularly the events that lead to apoptosis of endothelial cells during RAS development, remain elusive. Here, we report that RA could induce gene expressions of interferon (IFN) gamma and IL-1 beta in the peripheral blast cells of APL samples. By using human umbilical cord endothelial cells (HUVECs) and human lung microvascular endothelial cells (HLMVECs) in vitro, we observed that IFN gamma in combination with IL-1 beta exerted synergistic effect in inducing apoptosis of endothelial cells. In addition, RA treatment up-regulated the expression of CD38 antigen, an ectoenzyme involved in the metabolism of two calcium messengers, the cADPR and NAADP. RA-induced CD38 expression promoted intense attachment of maturing APL cells to the endothelial cells. Experimental data demonstrate that endothelial cells when treated with IFN gamma (10ng/ml) and IL-1 beta (10ng/ml) together undergo significant apoptosis with caspase 8 activation and CD38 expression. To our knowledge, this is the first report that demonstrates the regulation of IFN gamma gene expression in APL cells in response to RA treatment and the combined effect of cytokines and CD38 in driving endothelial cell into apoptosis. These events suggest a link between RA treatment and the development of retinoic acid syndrome and thus may offer novel approaches for controlling the development of RAS in APL patients.

scholarly journals Anticoagulant Effects of Synthetic Retinoids Mediated Via Different Receptors on Human Leukemia and Umbilical Vein Endothelial Cells

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1545-1551 ◽  
Author(s):  
Misako Shibakura ◽  
Takatoshi Koyama ◽  
Takako Saito ◽  
Koichi Shudo ◽  
Nobuyuki Miyasaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Umbilical Vein ◽  
Anticoagulant Effect ◽  
Leukemia Cells ◽  
Receptor Subtypes ◽  
Human Leukemia ◽  
U937 Cells ◽  
Nb4 Cells ◽  
Umbilical Vein Endothelial Cells

We recently found that retinoic acids (RAs) exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF ) expression in acute promyelocytic leukemia (APL) cells and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. In the present study, we have used several synthetic retinoids to determine which receptor subtypes are involved in the regulation of TM and TF expression in NB4 APL cells, U937 monoblastic leukemia cells, and human umbilical vein endothelial cells (HUVECs). Am80, which has no binding affinity for RARγ, and Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), upregulated TM and downregulated TF in NB4 and U937 cells, similar to all-trans RA (ATRA). A specific RARα antagonist, Ro41-5253, significantly suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells, and HUVECs. In contrast, only with preincubation with both RARα and RARβ antagonists was downregulation of TF by retinoids suppressed in NB4 cells. These findings indicate that the mechanism of transactivation and transrepression functions of RARs are distinct and also elucidate the major role of RARα in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperation of RARα and RARβ in TF downregulation by retinoids. They also indicate that binding to CRABP is not required for the anticoagulant effect of retinoids and that synthetic retinoids will prove very useful in controlling distinct targets, the TM and TF genes, at the level of transcription, and will permit the development of retinoids with a new type of anticoagulant effect.

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