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A major part of the anti-inflammatory effect of glucocorticoids
is attributable to their attenuation of the induction of genes whose
products mediate intercellular interactions, e.g. cytokines
and the inducible forms of prostaglandin synthase and nitric oxide
synthase. We hypothesized that (i) there exists a class of
immediate-early/primary response genes whose induction by inflammatory
agents, mitogens, and other stimuli is attenuated by glucocorticoids,
and (ii) the products of these glucocorticoid-attenuated response genes
(GARGs) function predominantly in paracrine cell processes. We
constructed a
Of the
five GARG cDNAs not previously known, one encodes a novel member of the
CXC chemokine family, designated LIX (LPS-induced CXC
chemokine). The predicted LIX protein has a 40-amino acid signal
sequence and a 92-amino acid mature peptide with a distinctive
COOH-terminal region. Surprisingly, segments of the 3`-untranslated
regions of LIX and two other CXC chemokines have substantially
greater nucleotide sequence homology than do their coding regions.
These segments may perform an unknown regulatory function. The LIX
message is strongly induced by LPS in fibroblasts, but not in
macrophages, suggesting that LIX may participate in the recruitment of
inflammatory cells by injured or infected tissue.
Volume 270,
Number 28,
Issue of July 14, pp. 16756-16765, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
cDNA library from transforming growth factor
1-pretreated murine Swiss 3T3 cells stimulated with
lipopolysaccharide (LPS) or serum in the presence of cycloheximide,
screened 15,000 plaques by differential hybridization, and cloned 12
LPS-induced, dexamethasone-attenuated cDNAs. Seven were previously
known. Six of these encode intercellular mediators (thrombospondin-1,
MCSF, JE/MCP-1, MARC/fic/MCP-3, crg2/IP-10, and cyr61); one encodes a
protein of unknown function (IRG2). Thus, a large majority of these
GARG cDNAs encode intercellular mediators, as hypothesized.
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