Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure

Martha M Monick; Linda S Powers; Noah S Butler; Gary W Hunninghake

doi:10.4049/jimmunol.171.5.2625

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Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure

Journal article

Open access

Peer reviewed

Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure

Martha M Monick, Linda S Powers, Noah S Butler and Gary W Hunninghake

The Journal of immunology (1950), Vol.171(5), pp.2625-2630

09/01/2003

DOI: 10.4049/jimmunol.171.5.2625

PMID: 12928415

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Abstract

These studies demonstrate that treatment of macrophages with lovastatin, a cholesterol-lowering drug that blocks farnesylation and geranylgeranylation of target proteins, increases LPS-induced TNF-alpha production. This is reversed by the addition of mevalonate, which bypasses the lovastatin block. Examination of membrane localization of RhoA, Cdc42, Rac1, and Ras demonstrated decreased membrane localization of the geranylgeranylated Rho family members (RhoA, Cdc42, and Rac1) with no change in the membrane localization of farnesylated Ras. LPS-induced TNF-alpha production in the presence of the Rho family-specific blocker (toxin B from Clostridium difficile) was significantly enhanced consistent with the lovastatin data. One intracellular signaling pathway that is required for TNF-alpha production by LPS is the extracellular signal-regulated kinase (ERK). Significantly, we found prolonged ERK activation after LPS stimulation of lovastatin-treated macrophages. When we inhibited ERK, we blocked the lovastatin-induced increase in TNF-alpha production. As a composite, these studies demonstrate a negative role for one or more Rho family GTPases in LPS-induced TNF-alpha production.

rho GTP-Binding Proteins - antagonists & inhibitors

Lovastatin - pharmacology

MAP Kinase Signaling System - immunology

Enzyme Activation - immunology

Immunosuppressive Agents - pharmacology

Macrophages - immunology

Immune Tolerance - drug effects

Mevalonic Acid - pharmacology

Cell Line

Enzyme Activation - drug effects

Mevalonic Acid - metabolism

rho GTP-Binding Proteins - physiology

Macrophages - enzymology

Up-Regulation - drug effects

Macrophages - metabolism

Animals

MAP Kinase Signaling System - drug effects

Mitogen-Activated Protein Kinases - antagonists & inhibitors

Mitogen-Activated Protein Kinases - physiology

Up-Regulation - immunology

Lipopolysaccharides - pharmacology

Macrophages - drug effects

Mice

Tumor Necrosis Factor-alpha - biosynthesis

Drug Combinations

Mitogen-Activated Protein Kinases - metabolism

Details

Title: Subtitle: Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure
Creators: Martha M Monick - Division of Pulmonary, Critical Care, and Occupational Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Room 100, Ekstein Medical Research Building, Iowa City, IA 52242, USA. martha-monick@uiowa.edu
Linda S Powers
Noah S Butler
Gary W Hunninghake
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.171(5), pp.2625-2630
Publisher: United States
DOI: 10.4049/jimmunol.171.5.2625
PMID: 12928415
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: ES 09607 / NIEHS NIH HHS HL 60316 / NHLBI NIH HHS RR 00059 / NCRR NIH HHS
Language: English
Date published: 09/01/2003
Academic Unit: Microbiology and Immunology; Internal Medicine
Record Identifier: 9984002389302771

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