Fcγ Receptor-mediated Mitogen-activated Protein Kinase Activation in Monocytes Is Independent of Ras*
- From the Immunology Department, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
Abstract
Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense, including phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Cross-linking of FcR with immune complexes leads, first to activation of protein-tyrosine kinases. The molecular events that follow and that transduce signals from these receptors to the nucleus are still poorly defined. We have investigated the signal transduction pathway from Fc receptors that leads to gene activation and production of cytokines in monocytes. Cross-linking of FcR, on the THP-1 monocytic cell line, by immune complexes resulted in both activation of the transcription factor NF-κB and interleukin 1 production. These responses were completely blocked by tyrosine kinase inhibitors. In contrast, expression of dominant negative mutants of Ras and Raf-1, in these cells, did not have any effect on FcR-mediated nuclear factor activation, suggesting that the mitogen-activated protein kinase (MAPK) signaling pathway was not used by these receptors. However, MAPK activation was easily detected by in vitro kinase assays, after FcR cross-linking with immune complexes. Using the specific MAPK/extracellular signal-regulated kinase kinase (MAPK kinase) inhibitor PD98059, we found that MAPK activation is necessary for FcR-dependent activation of the nuclear factor NF-κB. These results strongly suggest that the signaling pathway from Fc receptors leading to expression of different genes important to leukocyte biology, initiates with tyrosine kinases and requires MAPK activation; but in contrast to other tyrosine kinase receptors, FcR-mediated MAPK activation does not involve Ras and Raf.
Footnotes
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↵* This work was supported by Grant 2356P/N from Consejo Nacional de Ciencia y Tecnologia and Grant IN201797 from Direccíon General de Asuntos del Personal Académio, Universidad Nacional Autónoma de México.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Dept. of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apto. Postal 70228, Cd. Universitaria, México D.F. 04510, Mexico. Tel.: 52-5-622-3883; Fax: 52-5-622-3369; E-mail: carosal{at}servidor.unam.mx.
- Abbreviations:
- FcγR
-
receptor(s) for the Fc portion of immunoglobulin G molecules
- ERK
-
extracellular signal-regulated kinase
- HA-MAPK
-
MAPK containing the influenza hemagglutinin epitope tag
- IL-1
-
interleukin 1
- IL-8
-
interleukin 8
- MAPK
-
mitogen-activated protein kinase
- MAP
-
mitogen-activated protein
- MEK
-
MAPK/ERK kinase
- TNF
-
tumor necrosis factor
- MBP
-
myelin basic protein
- PAGE
-
polyacrylamide gel electrophoresis
- PBS
-
phosphate-buffered saline
- GFP
-
green fluorescent protein
- HA
-
hemagglutinin
- ELISA
-
enzyme-linked immunosorbent assay
- NK
-
natural killer
- NF-κB
-
nuclear factor κB
- IIC
-
insoluble immune complex.
-
- Received July 9, 1998.
