J Biol Chem, Vol. 275, Issue 10, 7403-7409, March 10, 2000

The Differential Time-course of Extracellular-regulated Kinase Activity Correlates with the Macrophage Response toward Proliferation or Activation^*

Annabel F. Valledor, Mónica Comalada^§, Jordi Xaus, and Antonio Celada^¶

From the Departament de Fisiologia (Biologia del Macròfag), Facultat de Biologia, and Fundació August Pi i Sunyer, Campus Bellvitge, Universitat de Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain

Bone marrow-derived macrophages proliferate in response to specific growth factors, including macrophage colony-stimulating factor (M-CSF). When stimulated with activating factors, such as lipopolysaccharide (LPS), macrophages stop proliferating and produce proinflammatory cytokines. Although triggering opposed responses, both M-CSF and LPS induce the activation of extracellular-regulated kinases (ERKs) 1 and 2. However, the time-course of ERK activation is different; maximal activation by M-CSF and LPS occurred after 5 and 15 min of stimulation, respectively. Granulocyte/macrophage colony-stimulating factor, interleukin 3, and TPA, all of which induced macrophage proliferation, also induced ERK activity, which was maximal at 5 min poststimulation. The use of PD98059, which specifically blocks ERK 1 and 2 activation, demonstrated that ERK activity was necessary for macrophage proliferation in response to these factors. The treatment with phosphatidylcholine-specific phospholipase C (PC-PLC) inhibited macrophage proliferation, induced the expression of cytokines, and triggered a pattern of ERK activation equivalent to that induced by LPS. Moreover, PD98059 inhibited the expression of cytokines induced by LPS or PC-PLC, thus suggesting that ERK activity is also required for macrophage activation by these two agents. Activation of the JNK pathway did not discriminate between proliferative and activating stimuli. In conclusion, our results allow to correlate the differences in the time-course of ERK activity with the macrophagic response toward proliferation or activation.

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^* This work was supported by Grants SAF 98/0102 and PM 98/0200 from the Comisión Interministerial de Ciencia y Tecnología (to A. C.).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.

Recipients of a fellowship from the Comissió Interdepartamental de Recerca i Innovació Tecnològica, Generalitat de Catalunya.

^§ Recipient of a fellowship from Fundació August Pi i Sunyer, Universitat de Barcelona.

^¶ To whom correspondence should be addressed. Tel.: 34-93-402-1555; Fax: 34-93-411-0358; E-mail: acelada@bio.ub.es.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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