RhoH/TTF negatively regulates leukotriene production in neutrophils.
Leukotriene B(4) (LTB(4)) is an important proinflammatory lipid mediator generated by neutrophils upon activation. GM-CSF stimulation is known to enhance agonist-mediated LTB(4) production of neutrophils within minutes, a process called "priming". In this study, we demonstrate that GM-CSF also limits the production of LTB(4) by neutrophils via a transcriptional mechanism at later time points. We identified hemopoietic-specific Ras homologous (RhoH)/translocation three four (TTF), which was induced following GM-CSF stimulation in neutrophils, as a key regulator in this process. Neutrophils derived from RhoH/TTF-deficient (Rhoh(-/-)) mice demonstrated increased LTB(4) production upon activation compared with normal mouse neutrophils. Moreover, neutrophils from cystic fibrosis patients expressed enhanced levels of RhoH/TTF and generated less LTB(4) upon activation compared with normal human neutrophils. Taken together, these data suggest that RhoH/TTF represents an inducible feedback inhibitor in neutrophils that is involved in the limitation of innate immune responses.
Daryadel
Arezoo
A
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Yousefi
Shida
S
Troi
David
D
Schmid
Inès
I
Schmidt-Mende
Jan
J
Mordasini
Carlo
C
Dahinden
Clemens A
CA
Ziemiecki
Andrew
A
Simon
Hans-Uwe
HU
D000818:Animals; D015153:Blotting, Western; D003550:Cystic Fibrosis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C496930:RhoH protein, mouse; D014157:Transcription Factors; D007975:Leukotriene B4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020741:rho GTP-Binding Proteins