RGD Reference Report - IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. - Rat Genome Database

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IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy.

Authors: Wigginton, JM  Gruys, E  Geiselhart, L  Subleski, J  Komschlies, KL  Park, JW  Wiltrout, TA  Nagashima, K  Back, TC  Wiltrout, RH 
Citation: Wigginton JM, etal., J Clin Invest. 2001 Jul;108(1):51-62.
RGD ID: 2290132
Pubmed: PMID:11435457   (View Abstract at PubMed)
PMCID: PMC209333   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI10128   (Journal Full-text)

Systemic administration of IL-12 and intermittent doses of IL-2 induce complete regression of metastatic murine renal carcinoma. Here, we show that overt tumor regression induced by IL-12/pulse IL-2 is preceded by recruitment of CD8(+) T cells, vascular injury, disrupted tumor neovascularization, and apoptosis of both endothelial and tumor cells. The IL-12/IL-2 combination synergistically enhances cell surface FasL expression on CD8(+) T lymphocytes in vitro and induces Fas and FasL expression within tumors via an IFN-gamma-dependent mechanism in vivo. This therapy also inhibits tumor neovascularization and induces tumor regression by mechanisms that depend critically on endogenous IFN-gamma production and an intact Fas/FasL pathway. The ability of IL-12/pulse IL-2 to induce rapid destruction of tumor-associated endothelial cells and regression of established metastatic tumors is ablated in mice with a dysregulated Fas/FasL pathway. The common, critical role for endogenous IFN-gamma and the Fas/FasL pathway in early antiangiogenic effects and in antitumor responses suggests that early, cytokine-driven innate immune mechanisms and CD8(+) T cell-mediated responses are interdependent. Definition of critical early molecular events engaged by IL-12/IL-2 may provide new perspective into optimal therapeutic engagement of a productive host-antitumor immune response.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
FASHumanrenal cell carcinoma  ISOFas (Mus musculus) RGD 
FASLGHumanrenal cell carcinoma  ISOFasl (Mus musculus) RGD 
FasRatrenal cell carcinoma  ISOFas (Mus musculus) RGD 
FasMouserenal cell carcinoma  IAGP  RGD 
FaslMouserenal cell carcinoma  IAGP  RGD 
FaslgRatrenal cell carcinoma  ISOFasl (Mus musculus) RGD 


Genes (Rattus norvegicus)
Fas  (Fas cell surface death receptor) Faslg  (Fas ligand)

Genes (Mus musculus)
Fas  (Fas cell surface death receptor) Fasl  (Fas ligand)

Genes (Homo sapiens)
FAS  (Fas cell surface death receptor) FASLG  (Fas ligand)