| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Biochemistry and Molecular Biology, and
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
Tissue hypoxemia is common in several pathological diseases, including vaso-occlusion in sickle cell disease and myocardial infarction. One finds increased presence of leukocytes during lung injury and at sites of inflammation in vascular endothelium. In this study, we used human pulmonary microvascular endothelial cells and human dermal microvascular endothelial immortalized cell line to delineate the cellular signaling mechanism of hypoxia- and CoCl2 (a mimetic of hypoxia)-induced IL-8 expression, and the latter’s role in chemotaxis of polmorphonuclear neutrophils. We show that hypoxia- and CoCl2-induced IL-8 mRNA and protein expression involved activation of PI3K/Akt and p38 MAPK, but not MEK kinase. Analysis of some transcription factors associated with IL-8 promoter revealed that hypoxia and CoCl2 increased DNA-binding activity of hypoxia-inducible factor-1
(HIF-1), NF-
B, and AP-1. In addition, we show that hypoxia- and CoCl2-induced IL-8 expression requires activation of HIF as demonstrated by the following: 1) EMSA; 2) transfection studies with IL-8 promoter reporter constructs with mutation in HIF-1 binding site; 3) attenuation of IL-8 expression by both HIF-1 small interfering RNA and R59949; 4) augmentation of IL-8 expression by either transfection with HIF-prolyl hydroxylase-2 small interfering RNA or overexpression of HIF-1; and 5) chromatin immunoprecipitation analysis. Moreover, conditioned medium from hypoxia-treated endothelial cells augmented chemotaxis of neutrophils, due to release of IL-8. These data indicate that hypoxia-induced signaling in vascular endothelium for transcriptional activation of IL-8 involves PI3K/Akt, p38 MAPK, and HIF-1. Pharmacological agents, which inhibit HIF-1, may possibly ameliorate inflammation associated with hypoxia in pathological diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant HL-070595.
2 A part of this work was presented by C.G., V.R., K.S.K., C.J., and V.K.K. at the Keystone Symposium "Hypoxia and Development, Physiology and Disease," Breckenridge, Colorado, January 16–21, 2006, Abstract 206.
3 K.S.K. and V.R. contributed equally to this study.
4 Address correspondence and reprint requests to Dr. Vijay K. Kalra, HMR 611, Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033. E-mail address: vkalra{at}usc.edu
5 Abbreviations used in this paper: SCD, sickle cell disease; ChIP, chromatin immunoprecipitation; CM, conditioned medium; Dn, dominant negative; EBM, endothelial basal medium; Epo, erythropoietin; HBEC, human brain endothelial cell; HDMVEC, human dermal microvascular endothelial cell; HIF, hypoxia-inducible factor; HPAEC, human pulmonary aortic endothelial cell; HPMVEC, human pulmonary microvascular endothelial cell; HRE, hypoxia response element; PHD, proline hydroxylase; PMN, polymorphonuclear neutrophil; RPA, RNase protection assay; siRNA, small interfering RNA; VHL, Von Hippel Lindau; wt, wild type; sc, scrambled.
This article has been cited by other articles:
|
|
 |
|
  L. Yuan, V. Nikolova-Krstevski, Y. Zhan, M. Kondo, M. Bhasin, L. Varghese, K. Yano, C. V. Carman, W. C. Aird, and P. Oettgen Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene Circ. Res., May 8, 2009; 104(9): 1049 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Acosta-Iborra, A. Elorza, I. M. Olazabal, N. B. Martin-Cofreces, S. Martin-Puig, M. Miro, M. J. Calzada, J. Aragones, F. Sanchez-Madrid, and M. O. Landazuri Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-{gamma} Production through the HIF-1{alpha} Transcription Factor J. Immunol., March 1, 2009; 182(5): 3155 - 3164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kaczmarek, R. E. Cachau, I. A. Topol, K. S. Kasprzak, A. Ghio, and K. Salnikow Metal Ions-Stimulated Iron Oxidation in Hydroxylases Facilitates Stabilization of HIF-1{alpha} Protein Toxicol. Sci., February 1, 2009; 107(2): 394 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Patel, C. S. Gonsalves, M. Yang, P. Malik, and V. K. Kalra Placenta growth factor induces 5-lipoxygenase-activating protein to increase leukotriene formation in sickle cell disease Blood, January 29, 2009; 113(5): 1129 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Brant and J. P. Fabisiak Nickel and the Microbial Toxin, MALP-2, Stimulate Proangiogenic Mediators from Human Lung Fibroblasts via a HIF-1{alpha} and COX-2-Mediated Pathway Toxicol. Sci., January 1, 2009; 107(1): 227 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Coleman, B. E. Rendon, M. Zhao, M.-W. Qian, R. Bucala, D. Xin, and R. A. Mitchell Cooperative Regulation of Non-Small Cell Lung Carcinoma Angiogenic Potential by Macrophage Migration Inhibitory Factor and Its Homolog, D-Dopachrome Tautomerase J. Immunol., August 15, 2008; 181(4): 2330 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Genin, A. Hasdai, D. Shinder, and M. Pines Hypoxia, Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha}), and Heat-Shock Proteins in Tibial Dyschondroplasia Poult. Sci., August 1, 2008; 87(8): 1556 - 1564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Patel, C. S. Gonsalves, P. Malik, and V. K. Kalra Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1{alpha} Blood, August 1, 2008; 112(3): 856 - 865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Denison, S. Battersby, A. E. King, M. Szuber, and H. N. Jabbour Prokineticin-1: A Novel Mediator of the Inflammatory Response in Third-Trimester Human Placenta Endocrinology, July 1, 2008; 149(7): 3470 - 3477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Ahn, E.-M. Koh, H.-S. Cha, Y. S. Lee, J. Kim, E.-K. Bae, and K.-S. Ahn Role of hypoxia-inducible factor-1{alpha} in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast-like synoviocytes Rheumatology, June 1, 2008; 47(6): 834 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rolny, L. Capparuccia, A. Casazza, M. Mazzone, A. Vallario, A. Cignetti, E. Medico, P. Carmeliet, P. M. Comoglio, and L. Tamagnone The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment J. Exp. Med., May 12, 2008; 205(5): 1155 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Raghuwanshi, M. W. Nasser, X. Chen, R. M. Strieter, and R. M. Richardson Depletion of {beta}-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer J. Immunol., April 15, 2008; 180(8): 5699 - 5706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dulak, A. Loboda, A. Jazwa, and A. Jozkowicz Comment on "A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells" J. Immunol., April 15, 2007; 178(8): 4707 - 4707. [Full Text] [PDF]
|
|
|
|
|
|
V. Rajgopal, C. Gonsalves, and V. K. Kalra Response to Comment on "A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells" J. Immunol., April 15, 2007; 178(8): 4707 - 4708. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
