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J. Biol. Chem., Vol. 278, Issue 34, 31853-31860, August 22, 2003
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GRP94/gp96 Elicits ERK Activation in Murine Macrophages
A ROLE FOR ENDOTOXIN CONTAMINATION IN NF-
B ACTIVATION AND NITRIC OXIDE PRODUCTION*
From the Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
Vaccination of mice with GRP94/gp96, the endoplasmic reticulum Hsp90,
elicits a variety of immune responses sufficient for tumor rejection and the
suppression of metastatic tumor progression. Macrophages are a prominent
GRP94/gp96 target, with GRP94/gp96 reported to activate macrophage NF-B
signaling and nitric oxide production, as well as the MAP kinase p38, JNK, and
ERK signaling cascades. However, recent studies report that heat shock protein
elicited macrophage activation is due, in large part, to contaminating
endotoxin. To examine the generality of this finding, we have investigated the
role of endotoxin in GRP94/gp96-elicited macrophage activation. We report that
GRP94/gp96 binds endotoxin in a high-affinity, saturable, and specific manner.
Low endotoxin calreticulin and GRP94/gp96 were purified, the latter using a
novel method of depyrogenation; this resulted in GRP94/gp96 and calreticulin
preparations with endotoxin levels substantially lower than those of
previously reported preparations. Low endotoxin GRP94/gp96 retained its native
conformation, ligand binding activity, and in vitro chaperone
function, yet did not activate macrophage NF-B signaling, nitric oxide
production or inducible nitric-oxide synthase production. Low endotoxin
GRP94/gp96 and calreticulin did, however, elicit a marked increase in ERK
phosphorylation at protein concentrations as low as 2 µg/ml. These results
are discussed with respect to current understanding of the contributions of
endotoxin and heat shock/chaperone proteins to the stimulation of innate
immune responses.
Received for publication, May 25, 2003
* These studies were supported by Grant DK53058 (to C. V. N.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 919-684-8948; Fax:
919-684-5481; E-mail:
c.nicchitta{at}cellbio.duke.edu.
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