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* Department of Microbiology and Immunology, McGill University,
Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montréal, and
Centre de Recherche en Infectiologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, and Faculty of Medicine, Université Laval, Québec City, Québec, Canada
S100A8 and S100A9 are intracellular calcium-binding proteins produced by myeloid cells that promote neutrophil/monocyte recruitment at inflamed tissues by enhancing attachment to endothelial cells. Although the intracellular functions of these proteins, i.e., myeloid-related proteins (MRP)-8 and MRP-14, are not completely understood, these proteins exhibit prominent extracellular cytokine-like functions and are considered reliable markers of inflammation in diverse diseases. As S100A8 and S100A9 have been reported to be rapidly released in response to components derived from infectious agents, we hypothesized that they play an important role in the modulation of key microbicidal phagocyte functions. In this study, we report for the first time that MRPs are powerful inducers of NO production by murine macrophages (M
). This increase in NO production was linked to an increased inducible NO synthase expression both at gene and protein level. This induction was concomitant with an important phosphorylation of SAPK/JNK, but also of MEK and ERK kinases. Upon stimulation with MRPs, NF-
B was rapidly translocated to the nucleus (30 min). When M were treated concomitantly with IFN-
, another activator of M functions, we observed a strong synergy in NO production, synergy that resulted from the engagement of exclusive signaling pathways: SAPK/JNK, ERK and NF-B were involved in signaling of MRPs, whereas IFN- uses the JAK/STAT pathway. This suggests that the synergy results from interactions of transcription factors in the promoter region. Finally, we observed this effect to be dependent on TLR4. Collectively, our study unravels the importance of MRPs as potent new inducers of M NO production.
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 an operating grant from the Canadian Institute of Health Research (CIHR) (to M.O.). P.P. is the recipient of a CIHR Canada Doctoral Award.
2 Address correspondence and reprint requests to Dr. Martin Olivier, Department of Microbiology and Immunology, Lyman Duff Medical Building Room 610, McGill University, 3775 University Street, Montréal, Québec, Canada H9S 3W6. E-mail address: martin.olivier{at}mcgill.ca
3 Abbreviations used in this paper: MRP, myeloid-related protein; iNOS, inducible NO synthase; M, macrophage; BMDM, bone marrow-derived macrophage; KO, knockout.
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