Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12.
The mechanisms by which interleukin-12 (IL-12) exerts antitumor effects have been difficult to dissect. In this study, we examined the potential contribution of the chemokines interferon-gamma-inducible protein-10 (IP-10) and Mig to the antitumor effects of IL-12. Using an athymic mouse model, local inoculations with IL-12 consistently produced tumor size reductions associated with characteristic tumor necrosis and vascular damage. These effects were indistinguishable from those produced by IP-10 or Mig injected locally in the same tumor model. Local and systemic treatment with IL-12 was associated with expression of the interferon-gamma (IFN-gamma), IP-10, and Mig genes and proteins in the tumor. Levels of IP-10 and Mig expression in the tumor, the liver, and the kidney were inversely correlated with tumor size. Administration in vivo of neutralizing antibodies to IP-10 and Mig reduced substantially the antitumor effects of IL-12 inoculated locally into the tumors. These results support the notion that IP-10 and Mig contribute to the antitumor effects of IL-12 through their inhibitory effects on tumor vasculature.
Kanegane
C
C
Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852-1448, USA.
Sgadari
C
C
Kanegane
H
H
Teruya-Feldstein
J
J
Yao
L
L
Gupta
G
G
Farber
J M
JM
Liao
F
F
Liu
L
L
Tosato
G
G
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000970:Antineoplastic Agents; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma