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RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils¹

Arezoo Daryadel^2,*, Shida Yousefi^2,*, David Troi^*, Inès Schmid^*, Jan Schmidt-Mende^*, Carlo Mordasini, Clemens A. Dahinden, Andrew Ziemiecki^3, and Hans-Uwe Simon^4,*

^* Institute of Pharmacology, Institute of Immunology, and Department of Clinical Research, University of Bern, Bern, Switzerland; and Tiefenau Hospital Bern, Bern Switzerland

Leukotriene B₄ (LTB₄) is an important proinflammatory lipid mediator generated by neutrophils upon activation. GM-CSF stimulation is known to enhance agonist-mediated LTB₄ production of neutrophils within minutes, a process called "priming". In this study, we demonstrate that GM-CSF also limits the production of LTB₄ 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 LTB₄ production upon activation compared with normal mouse neutrophils. Moreover, neutrophils from cystic fibrosis patients expressed enhanced levels of RhoH/TTF and generated less LTB₄ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants 310000-107526 (to H.-U.S.) and 310000-112078 (to S.Y.) from the Swiss National Science Foundation as well as by the OPO Foundation.

² These authors share first authorship.

³ Deceased. The remaining authors dedicate this work to the memory of Dr. Andrew Ziemiecki.

⁴ Address correspondence and reprint requests to Dr. Hans-Uwe Simon, Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. E-mail address: hus{at}pki.unibe.ch

⁵ Abbreviations used in this paper: LTB₄, leukotriene B₄; Cdc42, cell division cycle 42; CHX, cycloheximide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PKC, protein kinase C; Rac, Ras-related C3 botulinum toxin substrate; Ras, rat sarcoma; Rho, ras homologous; TTF, translocation three four.