PMID- 15684607
OWN - NLM
STAT- MEDLINE
DCOM- 20051020
LR  - 20200930
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 4
IP  - 2
DP  - 2005 Feb
TI  - Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment 
      with 5-fluorouracil: implications for anti-tumor immune response.
PG  - 231-41
AB  - Recently we observed that pancreatic carcinoma cell lines constitutively express 
      Interleukin-18 (IL-18). Bioactive IL-18 induces Interferon (IFN)-gamma 
      production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the 
      issue of anti-tumor effects of a tumor-derived cytokine and motivating a more 
      detailed analysis of IL-18 production in pancreatic carcinoma cells. This 
      analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil 
      [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic 
      cancer patients on IL-18 production and processing. IL-18 expression and 
      post-translational processing were determined using RT-PCR, immunoblot and ELISA 
      in pancreatic carcinoma cell lines and in tumor tissue and serum samples from 
      pancreatic carcinoma patients in the presence and absence of chemotherapeutic 
      drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues 
      associated with significantly elevated IL-18 levels in patients sera. 
      Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor 
      IL-18 with no apparent biological activity. However, the chemotherapeutic agent 
      5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of 
      proteolytically processed mature and degraded IL-18 species, respectively, in 
      Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells 
      induced IFN-gamma production by activated T cells in an IL-18-dependent manner. 
      Furthermore, adjuvant polychemotherapy including 5-FU significantly increased 
      serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. 
      Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent 
      processing of pro-IL18 leading to the secretion of biologically active IL-18. 
      These findings delineate a novel mechanism by which chemotherapeutic agents may 
      modulate local anti-tumor cell-mediated immune responses.
FAU - Carbone, Anna
AU  - Carbone A
AD  - Department of Gastroenterology and Clinical Nutrition, Azienda Ospedaliera San 
      Giovanni Battista, Molinette, Turin, Italy.
FAU - Rodeck, Ulrich
AU  - Rodeck U
FAU - Mauri, Francesco Angelo
AU  - Mauri FA
FAU - Sozzi, Michela
AU  - Sozzi M
FAU - Gaspari, Fabio
AU  - Gaspari F
FAU - Smirne, Carlo
AU  - Smirne C
FAU - Prati, Adriana
AU  - Prati A
FAU - Addeo, Alfredo
AU  - Addeo A
FAU - Novarino, Anna
AU  - Novarino A
FAU - Robecchi, Antonio
AU  - Robecchi A
FAU - Bertetto, Oscar
AU  - Bertetto O
FAU - Emanuelli, Giorgio
AU  - Emanuelli G
FAU - Bellone, Graziella
AU  - Bellone G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050202
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Interleukin-18)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antimetabolites, Antineoplastic/*therapeutic use
MH  - *Carcinoma, Pancreatic Ductal/drug therapy/immunology/metabolism
MH  - Case-Control Studies
MH  - Caspase 1/metabolism
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Culture Media, Conditioned
MH  - Enzyme Activation/*drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Fluorouracil/*therapeutic use
MH  - Humans
MH  - Immunoblotting
MH  - Interferon-gamma/metabolism
MH  - Interleukin-18/*metabolism
MH  - Male
MH  - Middle Aged
MH  - *Pancreatic Neoplasms/drug therapy/immunology/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Cells, Cultured
EDAT- 2005/02/03 09:00
MHDA- 2005/10/21 09:00
CRDT- 2005/02/03 09:00
PHST- 2005/02/03 09:00 [pubmed]
PHST- 2005/10/21 09:00 [medline]
PHST- 2005/02/03 09:00 [entrez]
AID - 1476 [pii]
AID - 10.4161/cbt.4.2.1476 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2005 Feb;4(2):231-41. doi: 10.4161/cbt.4.2.1476. Epub 2005 Feb 
      2.