Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.
In this study, we show that distinct compartmentalization patterns of the IL-1 molecules (IL-1alpha and IL-1beta), in the milieu of tumor cells that produce them, differentially affect the malignant process. Active forms of IL-1, namely precursor IL-1alpha (pIL-1alpha), mature IL-1beta (mIL-1beta), and mIL-1beta fused to a signal sequence (ssIL-1beta), were transfected into an established fibrosarcoma cell line, and tumorigenicity and antitumor immunity were assessed. Cell lines transfected with pIL-1alpha, which expresses IL-1alpha on the membrane, fail to develop local tumors and activate antitumor effector mechanisms, such as CTLs, NK cells, and high levels of IFN-gamma production. Cells transfected with secretable IL-1beta (mIL-1beta and ssIL-1beta) were more aggressive than wild-type and mock-transfected tumor cells; ssIL-1beta transfectants even exhibited metastatic tumors in the lungs of mice after i.v. inoculation (experimental metastasis). In IL-1beta tumors, increased vascularity patterns were observed. No detectable antitumor effector mechanisms were observed in spleens of mice injected with IL-1beta transfectants, mock-transfected or wild-type fibrosarcoma cells. Moreover, in spleens of mice injected with IL-1beta transfectants, suppression of polyclonal mitogenic responses (proliferation, IFN-gamma and IL-2 production) to Con A was observed, suggesting the development of general anergy. Histologically, infiltrating mononuclear cells penetrating the tumor were seen at pIL-1alpha tumor sites, whereas in mIL-1beta and ssIL-1beta tumor sites such infiltrating cells do not penetrate inside the tumor. This is, to our knowledge, the first report on differential, nonredundant, in vivo effects of IL-1alpha and IL-1beta in malignant processes; IL-1alpha reduces tumorigenicity by inducing antitumor immunity, whereas IL-1beta promotes invasiveness, including tumor angiogenesis, and also induces immune suppression in the host.
Song
Xiaoping
X
Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Voronov
Elena
E
Dvorkin
Tatyana
T
Fima
Eyal
E
Cagnano
Emanuela
E
Benharroch
Daniel
D
Shendler
Yaakov
Y
Bjorkdahl
Olle
O
Segal
Shraga
S
Dinarello
Charles A
CA
Apte
Ron N
RN
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014162:Transfection
D000276:Adjuvants, Immunologic; D007375:Interleukin-1