Expression of the chemokines IP-10 and Mig in IL-10 transduced tumors.
Several laboratories have reported marked tumor inhibition when the cytokine interleukin-10 (IL-10) is overexpressed as a transgene in a variety of tumor cells. To identify critical effector molecules, we compared the expression of the chemokine crg-2, the murine homolog of human inducible protein 10 (human IP-10) in murine mammary tumors derived from the transplantation of six IL-10 expressing clones of tumor cell line 66.1, parental 66.1, or 66-neo-cells. We observed increased levels of IP-10 mRNA in all IL-10-expressing tumors examined in comparison to 66-neo. IP-10 mRNA was not detected in parental 66.1 tumors. The closely related chemokine Mig (monokine induced by interferon-gamma [IFN-gamma]) was also induced in all IL-10-expressing tumors. Studies of cultured tumor cells in vitro show that mammary epithelial tumor cells, in the absence of host elements, can express IP-10 and Mig in response to induction with either lipopolysaccharide (LPS) or IFN-gamma alone. The combination of LPS plus IFN-gamma resulted in even greater induction of IP-10 RNA. The kinetics of induction differ somewhat for the two chemokines, with IP-10 showing slower induction and less rapid decline. Because both Mig and IP-10 are chemotactic for tumor-infiltrating lymphocytes, we examined the presence of CD4+ and CD8+ lymphocytes in these tumors. Consistent with the upregulation of Mig and IP-10, we saw significantly increased numbers of CD8+ cells and a lesser increase in CD4+ cells in tumors with elevated levels of both chemokines.
Greenebaum Cancer Center and Deparment of Pathology, University of Maryland, Baltimore, USA.
H
H
Sun
N
N
Kundu
R
R
Dorsey
M J
MJ
Jackson
A M
AM
Fulton
D000818:Animals; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism; D051379:Mice; D015846:Monokines / Q000235:genetics; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000302:isolation & purification; D014162:Transfection; D014407:Tumor Cells, Cultured
C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D015846:Monokines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016753:Interleukin-10; D007371:Interferon-gamma