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J. Biol. Chem., Vol. 277, Issue 45, 42808-42814, November 8, 2002
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From the The lung innate immune response to
lipopolysaccharide (LPS) coordinates cellular inflammation, mediator,
and protease release essential for host defense but deleterious in
asthma, chronic obstructive pulmonary disease, and cystic
fibrosis. In vitro, LPS signals to the transcription
factors NF
Granulocyte/Macrophage-Colony-stimulating Factor (GM-CSF)
Regulates Lung Innate Immunity to Lipopolysaccharide through
Akt/Erk Activation of NF
B and AP-1 in Vivo*
,, and Arthritis and Inflammation Research Center,
Department of Medicine, Cooperative Research Center (CRC) for Chronic
Inflammatory Diseases, Royal Melbourne Hospital, The University of
Melbourne, Parkville, VIC 3010, Australia and the Lung Disease Research
Laboratories, CRC for Chronic Inflammatory Diseases, Department of
Pharmacology, The University of Melbourne,
Parkville, VIC 3010, Australia
B via TLR4, MyD88, and IL-1R-associated kinase (IRAK), to
AP-1 by mitogen-activated protein (MAP) kinases, and via an alternate
route in IRAK-deficient mice, but the in vivo
lung signaling pathway(s) are not understood. We investigated the role
of Akt and Erk1/2 as LPS intensely stimulates granulocyte/macrophage-colony-stimulating factor (GM-CSF) release, and
neutralizing GM-CSF profoundly suppressed LPS-induced inflammation, suppressed expression and activity of lung proteases, significantly reduced GM-CSF and tumor necrosis factor 
(TNF) mRNA
expression, and dampened nuclear localization of both NFB (p50/65)
and AP-1. LPS markedly activated Akt and Erk1/2, but not p38, in a
GM-CSF-dependent manner in direct temporal association with
NFB and AP-1 activation. Pharmacological inhibition of Akt or Erk
activation in LPS-treated tracheal explants ex vivo
inhibited the release of GM-CSF. These data implicate
GM-CSF-dependent activation of Akt in the amplification of
this response and demonstrate the role of Erks rather than p38 in lung
LPS inflammatory responses. Inhibition of GM-CSF may be of therapeutic
benefit in inflammatory diseases in which LPS contributes to
lung damage.
*
This work was supported by the National Health and Medical
Research Council (NHMRC) of Australia and the Cooperative Research Center (CRC) for Chronic Inflammatory Diseases.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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