Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes.
The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-kappaB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation.
Das
Hiranmoy
H
Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Kumar
Ajay
A
Lin
Zhiyong
Z
Patino
Willmar D
WD
Hwang
Paul M
PM
Feinberg
Mark W
MW
Majumder
Pradip K
PK
Jain
Mukesh K
MK
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology; D002351:Carrageenan / Q000276:immunology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D002351:Carrageenan; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D018836:Inflammation Mediators; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C096161:KLF2 protein, human