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by LPS and IFN- attenuates the oxidative burst in macrophages
Department of Medicine IV-Experimental Division, University of Erlangen-Nürnberg, Faculty of Medicine, 91054 Erlangen, Germany
1Correspondence: University of Erlangen-Nürnberg, Faculty of Medicine, Loschgestrasse 8, 91054 Erlangen, Germany. E-mail: mfm423{at}rzmail.uni-erlangen.de
Desensitization of macrophages is important during the development of
sepsis. It was our intention to identify mechanisms that promote
macrophage deactivation upon contact with endotoxin (LPS) and
interferon-
(IFN-) in vitro. Macrophage activation
was achieved with 12-O-tetradecanoylphorbol 13-acetate (TPA), and the
oxidative burst (i.e., oxygen radical formation) was followed by
oxidation of the redox-sensitive dyes hydroethidine and
dichlorodihydrofluorescein diacetate. Prestimulation of macrophages for
15 h with a combination of LPS/IFN- attenuated oxygen radical
formation in response to TPA. Taking the anti-inflammatory properties
of the peroxisome proliferator-activating receptor (PPAR) into
consideration, we established activation of PPAR in response to
LPS/IFN- by an electrophoretic mobility shift, supershift, and a
reporter gene assay. The reporter contains a triple PPAR-responsive
element (PPRE) in front of a thymidine kinase minimal promoter driving
the luciferase gene. We demonstrated that PPRE decoy oligonucleotides,
supplied in front of LPS/IFN-, allowed a full oxidative burst to
recover upon TPA addition. Furthermore, we suppressed the oxidative
burst by using the PPAR agonists
15-deoxy-
12,14-prostaglandin J2, BRL 49653,
or ciglitazone. No effect was observed with WY 14643, a PPAR
agonist. We conclude that activation of PPARs, most likely PPAR,
promotes macrophage desensitization, thus attenuating the oxidative
burst. This process appears important during development of
sepsis.—von Knethen, A., Brüne, B. Delayed activation of PPAR
by LPS and IFN- attenuates the oxidative burst in macrophages.
Key Words: anti-inflammatory • sepsis • desensitization • respiratory burst
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