Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.
IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-kappa B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10+ IL-12- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-beta, may complement therapeutic strategies aimed at activating type I antitumor immune responses.
Sica
A
A
Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy. Sica@irfmn.mnegri.it
Saccani
A
A
Bottazzi
B
B
Polentarutti
N
N
Vecchi
A
A
van Damme
J
J
Mantovani
A
A
D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D005354:Fibrosarcoma / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000172:deficiency* / Q000378:metabolism; D009368:Neoplasm Transplantation; D011485:Protein Binding / Q000276:immunology; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000378:metabolism
D016328:NF-kappa B; D016753:Interleukin-10; D018664:Interleukin-12