Type I interferons inhibit the generation of tumor-associated macrophages.
Tumor-associated macrophages (TAM) are very abundant in tumors and are thought to play a major role in promoting tumor growth. The generation of TAM is positively regulated by several cytokines, including colony stimulating factor-1 (CSF-1) and monocyte chemoattractant protein-1 (CCL2). However, endogenous factors that suppress the generation of TAM within tumors have not been previously identified. An earlier study showed that endogenously produced type I interferons (IFN) suppressed tumor growth via their effects on hematopoietic cells rather than through direct effects on tumor cells. Therefore, we used mouse tumor models to investigate the effects of endogenously produced type I IFNs on the generation of TAM. We found using immunohistochemistry and flow cytometry that TAM density was significantly increased in tumors of mice lacking the type I IFN receptor (IFN-alpha/betaR(-/-) mice) compared to wild type mice. Moreover, the increase in TAM density was associated with a significant increase in tumor growth rate and angiogenesis. The phenotype of TAM was similar in IFN-alpha/betaR(-/-) mice and wild type mice and tumors in both mice produced similar amounts of CSF-1 and CCL2. However, in vitro assays indicated that low concentrations of type I IFNs significantly inhibited the generation of bone marrow macrophages in response to CSF-1. These findings indicate that endogenously produced type I IFNs suppress the generation of TAM, which may in turn account for inhibition of tumor growth and angiogenesis.
U'Ren
Lance
L
Department of Microbiology, Immunology, and Pathology, Colorado State University, Ft. Collins, CO 80523, USA.
Guth
Amanda
A
Kamstock
Debra
D
Dow
Steven
S
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D007370:Interferon Type I / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology* / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018932:Chemokine CCL2; D016207:Cytokines; D007370:Interferon Type I; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor