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Infection and Immunity, March 2000, p. 1235-1242, Vol. 68, No. 3
Department of Molecular Microbiology,
Washington University School of Medicine, St. Louis, Missouri 63110
Received 23 June 1999/Returned for modification 25 August
1999/Accepted 8 December 1999
We have investigated the synergistic interactions of a naturally
occurring peptidoglycan fragment (muramyl peptide) and bacterial endotoxin in the induction of inflammatory processes within respiratory epithelial cells, at the levels of both signal transduction events and
ultimate cellular metabolic effects. The source of the muramyl peptide
is Bordetella pertussis, the causative agent of the
respiratory disease pertussis. During log-phase growth, B. pertussis releases the muramyl peptide tracheal cytotoxin (TCT),
which has the structure N - acetylglucosaminyl - 1,6 - anhydro - N - acetylmuramyl - (L) - alanyl -
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Synergistic Epithelial Responses to Endotoxin and a
Naturally Occurring Muramyl Peptide

- (D) - glutamyl - meso - diaminopimelyl - (D) - alanine,
equivalent to a monomeric subunit of gram-negative bacterial peptidoglycan. When applied to hamster trachea epithelial (HTE) cells,
TCT and endotoxin were found to be highly synergistic in the induction
of interleukin-1
(IL-1
), type II (inducible) nitric oxide
synthase (iNOS), nitric oxide production, and inhibition of DNA
synthesis. Neither molecule alone significantly triggered these
responses. The serine/threonine protein kinase inhibitor H7 blocked
induction of both IL-1
and iNOS. More selective inhibitors of
protein kinase C, cyclic AMP-dependent protein kinase, and cyclic
GMP-dependent protein kinase were not capable of blocking the effects
of TCT and endotoxin, suggesting that the H7-inhibited component in
this pathway is not among the commonly described kinase targets of H7.
Treatment of HTE cells with exogenous IL-1 reproduced the induction of
iNOS and DNA synthesis inhibition caused by TCT and endotoxin. H7 was
not capable of interfering with effects caused by exogenous IL-1,
implying that the H7-sensitive step in the pathway is upstream of IL-1
protein production. Similar assays with the phorbol ester phorbol
myristate acetate indicate that it could effectively synergize with
endotoxin but not with TCT, suggesting that TCT and endotoxin induce
different signal transduction events that combine synergistically. The
synergy observed with TCT and endotoxin in epithelial cells is
significantly different from their interaction with other cell types,
revealing a unique inflammatory response by epithelial cells to these
natural bacterial products.
*
Corresponding author. Mailing address: Department of
Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-2742. Fax:
(314) 362-4879. E-mail: goldman{at}borcim.wustl.edu.
Present address: Milagen, Richmond, CA 94804.
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