Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.
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.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Can
C
Shi
Xiaobin
X
Zhang
Zhiping
Z
Chen
Karina
K
Sulaiman
Mark W
MW
Feinberg
Christie M
CM
Ballantyne
Mukesh K
MK
Jain
Daniel I
DI
Simon
D000595:Amino Acid Sequence; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D015536:Down-Regulation; D005340:Fibrinogen / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010587:Phagocytosis / Q000276:immunology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D039481:CD11b Antigen; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D016023:Integrins; D016177:Macrophage-1 Antigen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D005340:Fibrinogen; D013755:Tetradecanoylphorbol Acetate