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PMID: 15286807 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.

The Journal of clinical investigation ·Vol. 114 ·No. 3 ·2004-08-00 ·Pages 408-18

Shi C, Zhang X, Chen Z, Sulaiman K, Feinberg MW, Ballantyne CM, Jain MK, Simon DI

Abstract

The precise signals responsible for differentiation of blood-borne monocytes into tissue macrophages are incompletely defined. "Outside-in" signaling by integrins has been implicated in modulation of gene expression that affects cellular differentiation. Herein, using differential display PCR, we have cloned an 85-kDa forkhead transcription factor (termed Mac-1-regulated forkhead [MFH] and found subsequently to be identical to Foxp1) that is downregulated in beta(2)-integrin Mac-1-clustered compared with Mac-1-nonclustered monocytic THP-1 cells. MFH/Foxp1 is expressed in untreated HL60 cells, and its expression was markedly reduced during phorbol ester-induced monocyte differentiation, but not retinoic acid-induced granulocyte differentiation. Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. This was accompanied by decreased CD11b expression, cell adhesiveness, and phagocytosis. Using electromobility shift and reporter assays, we have established that MFH/Foxp1 binds to previously uncharacterized sites within the c-fms promoter and functions as a transcriptional repressor. Deficiency of Mac-1 is associated with altered regulation of MFH/Foxp1 and monocyte maturation in vivo. Taken together, these observations suggest that Mac-1 engagement orchestrates monocyte-differentiation signals by regulating the expression of the forkhead transcription repressor MFH/Foxp1. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.

MeSH Terms
Amino Acid Sequence Animals CD11b Antigen/immunology Cell Adhesion/immunology Cell Differentiation/drug effects Down-Regulation Fibrinogen/metabolism Forkhead Transcription Factors Gene Expression Regulation/immunology Genes, Reporter HL-60 Cells HeLa Cells Humans Integrins/metabolism Macrophage-1 Antigen/genetics,metabolism Mice Mice, Knockout Molecular Sequence Data Monocytes/immunology,metabolism NIH 3T3 Cells Phagocytosis/immunology Promoter Regions, Genetic Recombinant Fusion Proteins/metabolism Repressor Proteins/physiology Sequence Deletion Sequence Homology, Amino Acid Tetradecanoylphorbol Acetate/pharmacology
Chemicals
CD11b Antigen FOXP1 protein, human Forkhead Transcription Factors Foxp1 protein, mouse Integrins Macrophage-1 Antigen Recombinant Fusion Proteins Repressor Proteins Fibrinogen Tetradecanoylphorbol Acetate
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Shi Can
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhang Xiaobin
Chen Zhiping
Sulaiman Karina
Feinberg Mark W
Ballantyne Christie M
Jain Mukesh K
Simon Daniel I
References (45)
45 references, click to expand
  1. Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages.
    J Lipid Res. 1981 Sep;22(7):1131-41 PMID: 6271886
  2. Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.
    Proc Natl Acad Sci U S A. 1979 Jun;76(6):2779-83 PMID: 288066
  3. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion.
    J Clin Invest. 1988 Feb;81(2):624-9 PMID: 3339135
  4. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse.
    Proc Natl Acad Sci U S A. 1990 Jun;87(12):4828-32 PMID: 2191302
  5. Coupling of the adhesive receptor CD11b/CD18 to functional enhancement of effector macrophage tissue factor response.
    J Clin Invest. 1991 Jan;87(1):50-7 PMID: 1670636
  6. Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells.
    J Immunol. 1991 Jul 1;147(1):22-8 PMID: 1711076
  7. Antibody against the Leu-CAM beta-chain (CD18) promotes both LFA-1- and CR3-dependent adhesion events.
    J Immunol. 1992 Feb 15;148(4):1080-5 PMID: 1371129
  8. Integrins: versatility, modulation, and signaling in cell adhesion.
    Cell. 1992 Apr 3;69(1):11-25 PMID: 1555235
  9. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage.
    Cell. 1993 Jan 29;72(2):197-209 PMID: 7678779
  10. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands.
    J Cell Biol. 1993 Feb;120(4):1031-43 PMID: 7679388
  11. A structure-function analysis of transcriptional repression mediated by the WT1, Wilms' tumor suppressor protein.
    Oncogene. 1993 Jul;8(7):1713-20 PMID: 8510918
  12. Macrophage progenitors from mouse bone marrow and spleen differ in their expression of the Ly-6C differentiation antigen.
    J Immunol. 1993 Dec 1;151(11):6389-98 PMID: 8245473
  13. Hepatocyte nuclear factor 3/fork head or "winged helix" proteins: a family of transcription factors of diverse biologic function.
    Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10421-3 PMID: 8248124
  14. DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11583-7 PMID: 8265594
  15. Transcriptional activation modulated by homopolymeric glutamine and proline stretches.
    Science. 1994 Feb 11;263(5148):808-11 PMID: 8303297
  16. Distinct mouse bone marrow macrophage precursors identified by differential expression of ER-MP12 and ER-MP20 antigens.
    Eur J Immunol. 1994 Oct;24(10):2279-84 PMID: 7925556
  17. All-trans-retinoic acid induces simultaneously granulocytic differentiation and expression of inflammatory cytokines in HL-60 cells.
    Exp Hematol. 1995 Feb;23(2):117-25 PMID: 7530211
  18. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter.
    Mol Cell Biol. 1996 Mar;16(3):1231-40 PMID: 8622667
  19. A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation.
    Immunity. 1996 Dec;5(6):653-66 PMID: 8986723
  20. Structural identification of the hematopoietic progenitor antigen ER-MP12 as the vascular endothelial adhesion molecule PECAM-1 (CD31).
    Eur J Immunol. 1997 Feb;27(2):509-14 PMID: 9045924
  21. LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice.
    J Clin Invest. 1997 Mar 15;99(6):1340-50 PMID: 9077544
  22. Transcription factors, normal myeloid development, and leukemia.
    Blood. 1997 Jul 15;90(2):489-519 PMID: 9226149
  23. Integrin signaling: specificity and control of cell survival and cell cycle progression.
    Curr Opin Cell Biol. 1997 Oct;9(5):691-700 PMID: 9330873
  24. Transcription factors that regulate monocyte/macrophage differentiation.
    J Leukoc Biol. 1998 Apr;63(4):405-17 PMID: 9544570
  25. Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes.
    J Immunol. 1998 Aug 1;161(3):1462-70 PMID: 9686612
  26. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits.
    Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10134-9 PMID: 9707613
  27. Antibody-induced engagement of beta2 integrins in human neutrophils causes a rapid redistribution of cytoskeletal proteins, Src-family tyrosine kinases, and p72syk that precedes de novo actin polymerization.
    J Leukoc Biol. 1998 Sep;64(3):401-8 PMID: 9738668
  28. GATA-3-dependent enhancer activity in IL-4 gene regulation.
    J Immunol. 1998 Oct 15;161(8):3822-6 PMID: 9780146
  29. Cloning and characterization of a novel zinc finger transcriptional repressor. A direct role of the zinc finger motif in repression.
    J Biol Chem. 1999 May 21;274(21):14678-84 PMID: 10329662
  30. Commitment to the monocytic lineage occurs in the absence of the transcription factor PU.1.
    Blood. 1999 May 1;93(9):2849-58 PMID: 10216079
  31. Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty.
    J Clin Invest. 2000 Feb;105(3):293-300 PMID: 10675355
  32. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity.
    Nature. 2000 Apr 6;404(6778):617-21 PMID: 10766246
  33. Vitamin A deficiency in mice causes a systemic expansion of myeloid cells.
    Blood. 2000 Jun 1;95(11):3349-56 PMID: 10828015
  34. Engagement of CD11b and CD11c beta2 integrin by antibodies or soluble CD23 induces IL-1beta production on primary human monocytes through mitogen-activated protein kinase-dependent pathways.
    Blood. 2000 Jun 15;95(12):3868-77 PMID: 10845922
  35. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18).
    J Exp Med. 2000 Jul 17;192(2):193-204 PMID: 10899906
  36. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors.
    J Biol Chem. 2001 Jul 20;276(29):27488-97 PMID: 11358962
  37. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.
    Oncogene. 2001 Jul 27;20(33):4519-27 PMID: 11494147
  38. Leukocyte integrin Mac-1 recruits toll/interleukin-1 receptor superfamily signaling intermediates to modulate NF-kappaB activity.
    Circ Res. 2001 Nov 9;89(10):859-65 PMID: 11701612
  39. The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.
    Cancer Res. 2001 Dec 15;61(24):8820-9 PMID: 11751404
  40. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects.
    Blood. 2002 Jan 1;99(1):111-20 PMID: 11756160
  41. NF-kappaB inhibits transcription of the H(+)-K(+)-ATPase alpha(2)-subunit gene: role of histone deacetylases.
    Am J Physiol Renal Physiol. 2002 Nov;283(5):F904-11 PMID: 12372765
  42. Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.
    J Biol Chem. 2003 Jul 4;278(27):24259-68 PMID: 12692134
  43. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B.
    Mol Cell. 2004 Mar 26;13(6):853-65 PMID: 15053878
  44. Identification of a novel NF-kappaB-binding site with regulation of the murine alpha2(I) collagen promoter.
    J Biol Chem. 2004 Apr 9;279(15):15639-44 PMID: 14722113
  45. Macrophages in T and B cell compartments and other tissue macrophages recognized by monoclonal antibody MOMA-2. An immunohistochemical study.
    Scand J Immunol. 1987 Dec;26(6):653-61 PMID: 3321409
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI21100
Published
2004-08-00
Pages
408-18
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC484980
Subset
IM
Grants
NIDDK NIH HHS · R01 DK55656 · United States
NHLBI NIH HHS · R01 HL03747 · United States
NHLBI NIH HHS · R01 HL075427 · United States
NHLBI NIH HHS · R01 HL73852 · United States
NHLBI NIH HHS · K08 HL067755 · United States
NHLBI NIH HHS · R01 HL073852 · United States
NHLBI NIH HHS · K08 HL67755 · United States
NHLBI NIH HHS · R01 HL057506 · United States
NHLBI NIH HHS · R01 HL57506 · United States
External Links
PubMed source DOI: 10.1172/JCI21100 PMC Full Text View journal details
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