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,
*
Istituto di Patologia Generale, Università degli Studi di Milano, Milan, Italy;
Pharma Division, Preclinical Centre National Scientifique Research, F. Hoffmann-La Roche, Basel, Switzerland;
Department of Biotechnology and Biomedical Sciences, Section of General Pathology and Immunology, University of Brescia, Brescia, Italy;
Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy
The gene expression profile induced by the CC chemokine ligand
(CCL) 5/RANTES in human monocytes was examined using the
oligonucleotide array technology. Of 5600 transcripts examined, 42 were
consistently induced by CCL5, and none were suppressed.
Chemokine-inducible transcripts could be clustered in functional
groups, including selected cytokines and receptors (e.g., IL-1
,
CCL2/monocyte chemotactic protein-1, and the CCL5 receptor CCR1) and
molecules involved in extracellular matrix recognition and digestion
(e.g., CD44 splice transcripts, urokinase-type plasminogen activator
receptor, matrix metalloprotease (MMP)-9 , and MMP-19). Transcript
expression, confirmed by quantitative real-time PCR analysis for
selected genes, was associated with protein induction for some (e.g.,
CCL2), but not all (e.g., IL-1), transcripts examined. The
chemokine-induced gene profile was distinct from that activated by LPS,
a prototypic phagocyte activator. Although certain transcripts were
stimulated by both agonists (e.g., IL-1 and CCL2), others were
induced only by either LPS (e.g., TNF-
and IL-6) or CCL5 (e.g.,
MMP-19) or were divergently regulated (e.g., CCR1). Thus, CCL5, a
prototypic CC inflammatory chemokine, activates a restricted
transcriptional program in monocytes distinct from that induced by the
prototypic pathogen-derived proinflammatory stimulant LPS.
Chemokine-induced chemokines production could represent a novel
amplification loop of leukocyte recruitment, while a subset of
chemokine-inducible transcripts could be involved in monocyte
extravasation and tissue invasion.
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