G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9.
Certain chemokines possess anti-angiogenic and antibacterial activity, in addition to their ability to recruit leukocytes. Herein, we demonstrate that CXCL9/MIG induces the expression, by a monocytic cell line and peripheral blood mononuclear cells, of a variety of chemokines including CXCL8/IL-8, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL2/MCP-1 in a pertussis toxin insensitive manner. Similarly, another cationic chemokine CCL20/MIP-3alpha, but not the non-cationic chemokines CCL2 or CCL3, stimulated monocytic cells to produce substantial amounts of CXCL8 and CCL3. Microarray experiments demonstrated that CXCL9, but not CCL2, induced the expression of hundreds of genes, many of which have known or proposed immunomodulatory functions. Induction of CXCL8 required the p38 and ERK1/2 mitogen-activated protein kinases but not NFkappaB, JAK-STAT or JNK signaling pathways. These results collectively demonstrate that CXCL9 has immunomodulatory functions that are not mediated through a G-protein coupled receptor and may possess additional roles in host defenses against infection.
Gong
Jiang-Hong
JH
Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
Nicholls
Erin F
EF
Elliott
Melissa R
MR
Brown
Kelly L
KL
Hokamp
Karsten
K
Roche
Fiona M
FM
Cheung
Charles Y K
CY
Falsafi
Reza
R
Brinkman
Fiona S L
FS
Bowdish
D M E
DM
Hancock
Robert E W
RE
D002460:Cell Line; D018932:Chemokine CCL2 / Q000276:immunology; D054418:Chemokine CCL20 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D037342:Pertussis Toxin / Q000276:immunology; D054388:Receptors, CCR / Q000235:genetics / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018932:Chemokine CCL2; D054418:Chemokine CCL20; D054370:Chemokine CXCL9; D007155:Immunologic Factors; D054388:Receptors, CCR; D043562:Receptors, G-Protein-Coupled; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases