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PMID: 15235127 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 28 ·2004-07-13 ·Pages 10440-5

Kong T, Eltzschig HK, Karhausen J, Colgan SP, Shelley CS

Abstract

Inflammatory responses are associated with significant changes in tissue metabolism. In particular, metabolic shifts during inflammation can result in significant tissue hypoxia, with resultant induction of hypoxia-responsive genes. Given this association, we hypothesized that leukocyte functional responses are influenced by hypoxia. Initial experiments revealed that exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelia. Such increases were transcription-dependent and were blocked by antibodies directed against beta2, but not beta1, integrins. Analysis of beta2 integrin mRNA and protein in U937 cells revealed a 5- to 6-fold increase with hypoxia. Extension of this analysis to hypoxic human whole blood revealed prominent induction of beta2 integrin mRNA and protein ex vivo. Furthermore, murine beta2 integrin mRNA was found to be significantly induced during hypoxia in vivo. Subsequent studies identified a binding site for hypoxia-inducible factor 1 (HIF-1) in the CD18 gene. This gene encodes the subunit common to all four known types of beta2 integrin heterodimer. HIF-1 binding was demonstrated in vivo, and mutational analysis of the HIF-1 site within the CD18 promoter resulted in a loss of hypoxia inducibility. Taken together, these results demonstrate that hypoxia induces leukocyte beta2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1.

MeSH Terms
Base Sequence CD18 Antigens/genetics,metabolism Cell Adhesion/immunology DNA-Binding Proteins/metabolism Endothelium, Vascular/cytology Gene Expression/immunology Humans Hypoxia/immunology,physiopathology Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Leukocytes/cytology,physiology Membrane Proteins/genetics,metabolism Molecular Sequence Data Nuclear Proteins/metabolism Promoter Regions, Genetic RNA, Messenger/analysis Transcription Factors Transcriptional Activation/immunology U937 Cells
Chemicals
CD18 Antigens DNA-Binding Proteins HIF1A protein, human Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Membrane Proteins Nuclear Proteins RNA, Messenger Transcription Factors
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kong Tianqing
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Eltzschig Holger K
Karhausen Jorn
Colgan Sean P
Shelley C Simon
References (58)
58 references, click to expand
  1. Therapeutic targets for hypoxia-elicited pathways.
    Pharm Res. 1999 Oct;16(10):1498-505 PMID: 10554089
  2. A novel role for the hypoxia inducible transcription factor HIF-1alpha: critical regulation of inflammatory cell function.
    Cell Cycle. 2003 May-Jun;2(3):192-3 PMID: 12734422
  3. The role of neutrophils in myocardial ischemia-reperfusion injury.
    Cardiovasc Res. 1999 Sep;43(4):860-78 PMID: 10615413
  4. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression.
    Crit Rev Biochem Mol Biol. 2000;35(2):71-103 PMID: 10821478
  5. Hypoxia, HIF-1, and the pathophysiology of common human diseases.
    Adv Exp Med Biol. 2000;475:123-30 PMID: 10849654
  6. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.
    EMBO J. 2000 Aug 15;19(16):4298-309 PMID: 10944113
  7. HIF-1 and human disease: one highly involved factor.
    Genes Dev. 2000 Aug 15;14(16):1983-91 PMID: 10950862
  8. Avidity regulation of integrins: the driving force in leukocyte adhesion.
    Curr Opin Cell Biol. 2000 Oct;12(5):542-7 PMID: 10978887
  9. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes.
    Hum Mol Genet. 2001 Mar 1;10(5):445-56 PMID: 11181568
  10. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide.
    J Biol Chem. 2001 Jan 19;276(3):2292-8 PMID: 11056166
  11. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
    Science. 2001 Apr 20;292(5516):468-72 PMID: 11292861
  12. Phosphoinositide 3-kinase modulation of beta(3)-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration.
    Blood. 2001 May 15;97(10):3251-8 PMID: 11342456
  13. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.
    J Exp Med. 2001 May 7;193(9):1027-34 PMID: 11342587
  14. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus.
    Cell. 2001 Oct 5;107(1):1-3 PMID: 11595178
  15. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL.
    Nature. 2002 Jun 27;417(6892):975-8 PMID: 12050673
  16. Anoxia/reoxygenation-induced leukocyte-endothelial cell interactions.
    Free Radic Biol Med. 2002 Aug 15;33(4):427-32 PMID: 12160924
  17. Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.
    J Clin Invest. 2002 Oct;110(7):993-1002 PMID: 12370277
  18. A new mathematical model for relative quantification in real-time RT-PCR.
    Nucleic Acids Res. 2001 May 1;29(9):e45 PMID: 11328886
  19. Implications of hypoxia on mucosal barrier function.
    Cell Mol Biol (Noisy-le-grand). 2003 Feb;49(1):77-87 PMID: 12839339
  20. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability.
    Proc Natl Acad Sci U S A. 1988 Feb;85(4):1105-8 PMID: 3422482
  21. Quantitation of intracellular Mac-1 (CD11b/CD18) pools in human neutrophils.
    J Leukoc Biol. 1988 Dec;44(6):535-44 PMID: 2903896
  22. Human leukocyte adhesion deficiency: molecular basis for a defective immune response to infections of the skin.
    Curr Probl Dermatol. 1989;18:106-15 PMID: 2663358
  23. Vectorial targeting of apical and basolateral plasma membrane proteins in a human adenocarcinoma epithelial cell line.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9313-7 PMID: 2687880
  24. Structure and function of the leukocyte adhesion molecules CD11/CD18.
    Blood. 1990 Mar 1;75(5):1037-50 PMID: 1968349
  25. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response.
    Immunol Rev. 1990 Apr;114:145-80 PMID: 1973407
  26. Structure and function of leukocyte integrins.
    Immunol Rev. 1990 Apr;114:181-217 PMID: 2196220
  27. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil.
    Br J Surg. 1991 Jun;78(6):651-5 PMID: 2070226
  28. The promoter of the CD11b gene directs myeloid-specific and developmentally regulated expression.
    Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10525-9 PMID: 1683702
  29. The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter.
    J Biol Chem. 1993 Mar 5;268(7):5014-20 PMID: 8095266
  30. The Sp1 transcription factor binds the CD11b promoter specifically in myeloid cells in vivo and is essential for myeloid-specific promoter activity.
    J Biol Chem. 1993 Apr 15;268(11):8230-9 PMID: 8096519
  31. Identification of cell-specific and developmentally regulated nuclear factors that direct myeloid and lymphoid expression of the CD11a gene.
    Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5364-8 PMID: 8099450
  32. The human beta 2 integrin CD18 promoter consists of two inverted Ets cis elements.
    Mol Cell Biol. 1994 Apr;14(4):2604-15 PMID: 7511209
  33. CD18 (beta 2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity.
    Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):801-5 PMID: 7846055
  34. Regulation of erythropoietin production. New insights into molecular mechanisms of oxygen homeostasis.
    Hematol Oncol Clin North Am. 1994 Oct;8(5):863-84 PMID: 7852211
  35. Seeding of vascular grafts with an immortalized human dermal microvascular endothelial cell line.
    Angiology. 1995 Feb;46(2):107-13 PMID: 7702194
  36. Hypoxia-induced alterations of neutrophil membrane receptors.
    J Surg Res. 1995 Jul;59(1):141-5 PMID: 7630118
  37. Leukocyte responses to hypoxic/ischemic conditions.
    New Horiz. 1996 May;4(2):179-83 PMID: 8774794
  38. Regulation of leukocyte integrin function: affinity vs. avidity.
    J Cell Biochem. 1996 Jun 15;61(4):554-61 PMID: 8806078
  39. Induction of the CD11b gene during activation of the monocytic cell line U937 requires a novel nuclear factor MS-2.
    J Immunol. 1996 Dec 15;157(12):5597-605 PMID: 8955212
  40. Hypoxia enhances induction of endothelial ICAM-1: role for metabolic acidosis and proteasomes.
    Am J Physiol. 1997 Nov;273(5 Pt 1):C1571-80 PMID: 9374642
  41. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.
    Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92 PMID: 9653127
  42. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.
    Nature. 1998 Jul 30;394(6692):485-90 PMID: 9697772
  43. Neutrophil-derived 5'-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A2B receptor activation.
    J Exp Med. 1998 Oct 19;188(8):1433-43 PMID: 9782120
  44. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
    Nature. 1999 May 20;399(6733):271-5 PMID: 10353251
  45. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
    Cell. 2001 Oct 5;107(1):43-54 PMID: 11595184
  46. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands.
    Curr Opin Hematol. 2002 Jan;9(1):30-5 PMID: 11753075
  47. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.
    Science. 2002 Feb 1;295(5556):858-61 PMID: 11823643
  48. During differentiation of the monocytic cell line U937, Pur alpha mediates induction of the CD11c beta 2 integrin gene promoter.
    J Immunol. 2002 Apr 15;168(8):3887-93 PMID: 11937543
  49. Neutrophil-derived glutamate regulates vascular endothelial barrier function.
    J Biol Chem. 2002 Apr 26;277(17):14801-11 PMID: 11847215
  50. Leukocyte transendothelial migration: a junctional affair.
    Semin Immunol. 2002 Apr;14(2):105-13 PMID: 11978082
  51. Regional manifestations and control of the immune system.
    FASEB J. 2002 Jun;16(8):849-56 PMID: 12039867
  52. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.
    Cancer Res. 2002 Jun 15;62(12):3387-94 PMID: 12067980
  53. Neutrophil transepithelial migration: evidence for sequential, contact-dependent signaling events and enhanced paracellular permeability independent of transjunctional migration.
    J Immunol. 2002 Jul 1;169(1):476-86 PMID: 12077279
  54. GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells.
    Blood. 2003 Jan 1;101(1):311-7 PMID: 12485937
  55. Science review: redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for hypoxia-inducible factor-1alpha.
    Crit Care. 2003 Feb;7(1):47-54 PMID: 12617740
  56. HIF-1alpha is essential for myeloid cell-mediated inflammation.
    Cell. 2003 Mar 7;112(5):645-57 PMID: 12628185
  57. CD11c gene expression in hairy cell leukemia is dependent upon activation of the proto-oncogenes ras and junD.
    Blood. 2003 May 15;101(10):4033-41 PMID: 12576324
  58. Macrophage responses to hypoxia: relevance to disease mechanisms.
    J Leukoc Biol. 1999 Dec;66(6):889-900 PMID: 10614769
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0401339101
Published
2004-07-13
Epub
2004-00-02
Pages
10440-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC478589
Subset
IM
Grants
NIDDK NIH HHS · P01 DK050305 · United States
NHLBI NIH HHS · R01 HL060569 · United States
NIDDK NIH HHS · R01 DK050189 · United States
NIDDK NIH HHS · R29 DK050189 · United States
NIDDK NIH HHS · R37 DK050189 · United States
NIDDK NIH HHS · DK50189 · United States
NHLBI NIH HHS · HL60569 · United States
NIDDK NIH HHS · DK50305 · United States
External Links
PubMed source DOI: 10.1073/pnas.0401339101 PMC Full Text View journal details
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