| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Activation by H2O2: Relevance in Inflammation and Synergy with TNF-
1
,
,
* Grupo de Bioquímica dos Oxidantes e Antioxidantes, Centro de Química e Bioquímica and
Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal;
Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal; and
Computational Biology Services, Lisboa, Portugal
Although the germicide role of H2O2 released during inflammation is well established, a hypothetical regulatory function, either promoting or inhibiting inflammation, is still controversial. In particular, after 15 years of highly contradictory results it remains uncertain whether H2O2 by itself activates NF-
B or if it stimulates or inhibits the activation of NF-B by proinflammatory mediators. We investigated the role of H2O2 in NF-B activation using, for the first time, a calibrated and controlled method of H2O2 delivery—the steady-state titration—in which cells are exposed to constant, low, and known concentrations of H2O2. This technique contrasts with previously applied techniques, which disrupt cellular redox homeostasis and/or introduce uncertainties in the actual H2O2 concentration to which cells are exposed. In both MCF-7 and HeLa cells, H2O2 at extracellular concentrations up to 25 µM did not induce significantly per se NF-B translocation to the nucleus, but it stimulated the translocation induced by TNF-
. For higher H2O2 doses this stimulatory role shifts to an inhibition, which may explain published contradictory results. The stimulatory role was confirmed by the observation that 12.5 µM H2O2, a concentration found during inflammation, increased the expression of several proinflammatory NF-B-dependent genes induced by TNF- (e.g., IL-8, MCP-1, TLR2, and TNF-). The same low H2O2 concentration also induced the anti-inflammatory gene coding for heme oxygenase-1 (HO-1) and IL-6. We propose that H2O2 has a fine-tuning regulatory role, comprising both a proinflammatory control loop that increases pathogen removal and an anti-inflammatory control loop, which avoids an exacerbated harmful inflammatory response.
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 supported by Grant POCTI/BCI/42245/2001 from Fundação para a Ciência e a Technologia-Portugal. V.d.O.M. and F.A. acknowledge fellowships BD/16681/2004 and BPD/11487/2002 from Fundação para a Ciência e a Technologia-Portugal.
2 Address correspondence and reprint requests to Dr. Virgínia de Oliveira-Marques, Centro de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal. E-mail address: vmmarques{at}fc.ul.pt
3 Abbreviations used in this paper: ROS, reactive oxygen species; Egr-1, early growth response-1; H2O2, hydrogen peroxide; [H2O2]ss, H2O2 steady-state concentration; HO-1, heme oxygenase-1; GPR89, G-protein-coupled receptor 89.
4 The online version of this article contains supplemental material.
This article has been cited by other articles:
|
|
 |
|
  N. Nakao, T. Kurokawa, T. Nonami, G. Tumurkhuu, N. Koide, and T. Yokochi Hydrogen peroxide induces the production of tumor necrosis factor-{alpha} in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase Innate Immunity, June 1, 2008; 14(3): 190 - 196. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Aydin, S. Signorelli, T. Lechleitner, M. Joannidis, C. Pleban, P. Perco, W. Pfaller, and P. Jennings Influence of microvascular endothelial cells on transcriptional regulation of proximal tubular epithelial cells Am J Physiol Cell Physiol, February 1, 2008; 294(2): C543 - C554. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
