PMID- 12014674
OWN - NLM
STAT- MEDLINE
DCOM- 20020627
LR  - 20210103
IS  - 0250-7005 (Print)
IS  - 0250-7005 (Linking)
VI  - 22
IP  - 2A
DP  - 2002 Mar-Apr
TI  - Interleukin-12 and interleukin-18 induce indoleamine 2,3-dioxygenase (IDO) 
      activity in human osteosarcoma cell lines independently from interferon-gamma.
PG  - 931-6
AB  - PURPOSE: In this study we evaluated the ability of inducing activation of the 
      enzyme indoleamine 2,3-dioxygenase (IDO) for the development of a new adjuvant 
      therapy of osteosarcomas. The pathway that has described in the literature states 
      that IDO activity is elevated by IFN-gamma. This mechanism is important because 
      the increased IDO activation induces an intracellular degradation of the 
      essential amino acid tryptophan and thereby activates apoptosis in human 
      osteosarcoma cells. MATERIALS AND METHODS: Four different well-established human 
      osteosarcoma cell lines (MNNG/HOS, KHOS-240, HOS and MG-63) were investigated in 
      vitro. Several cytokines were tested for their ability to induce IDO activity. 
      However special emphasis was placed to evaluate the synergistic effects of 
      Interleukin-12 (IL-12) in combination with Interleukin-18 (IL-18). In the first 
      series of experiments IDO induction was investigated by direct application of the 
      cytokines IFN-gamma, TNF-alpha, IL-12 and IL-18 in different concentrations. 
      Secondly, the increase of IDO expression from osteosarcoma cell lines was 
      analysed in the presence of activated lymphocytes with or without cytokine 
      application. RESULTS: Our results demonstrated that the combined application of 
      IL-12 and IL-18 enhanced IDO activity in the human osteosarcoma cell lines HOS 
      and MG-63, in the presence of activated lymphocytes. In the absence of activated 
      lymphocytes, no significant enhancement could be detected. In all our experiments 
      the increase in IDO expression was only partly inhibited by blocking INF-gamma. 
      CONCLUSION: The presented study demonstrates that IL-12 and IL-18, or even more a 
      combined application of both cytokines, induce IDO expression besides the known 
      pathway via IFN-gamma. These mechanisms have been shown herein for the first time 
      in human osteosacoma cell lines. Since IDO expression could still be shown after 
      complete blocking of IFN-gamma, we conclude that at least a second pathway is 
      responsible for inducing IDO activity. This is in contrast to the present 
      knowledge about IDO activation.
FAU - Liebau, Christian
AU  - Liebau C
AD  - Department of Orthopaedic Surgery, Ernst-Moritz-Arndt-University of Greifswald, 
      Germany.
FAU - Baltzer, Axel W A
AU  - Baltzer AW
FAU - Schmidt, Sebastian
AU  - Schmidt S
FAU - Roesel, Christian
AU  - Roesel C
FAU - Karreman, Christiaan
AU  - Karreman C
FAU - Prisack, Johannes Bernd
AU  - Prisack JB
FAU - Bojar, Hans
AU  - Bojar H
FAU - Merk, Harry
AU  - Merk H
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
RN  - 0 (Culture Media)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Interleukin-18)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 187348-17-0 (Interleukin-12)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
SB  - IM
MH  - Bone Neoplasms/*enzymology
MH  - Coculture Techniques
MH  - Culture Media
MH  - Drug Synergism
MH  - Enzyme Induction/drug effects
MH  - Humans
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase
MH  - Interferon-gamma/*pharmacology
MH  - Interleukin-12/*pharmacology
MH  - Interleukin-18/*pharmacology
MH  - Lymphocyte Activation
MH  - Lymphocytes/cytology/drug effects
MH  - Osteosarcoma/*enzymology
MH  - Recombinant Proteins/pharmacology
MH  - Tryptophan Oxygenase/*biosynthesis/metabolism
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2002/05/17 10:00
MHDA- 2002/06/28 10:01
CRDT- 2002/05/17 10:00
PHST- 2002/05/17 10:00 [pubmed]
PHST- 2002/06/28 10:01 [medline]
PHST- 2002/05/17 10:00 [entrez]
PST - ppublish
SO  - Anticancer Res. 2002 Mar-Apr;22(2A):931-6.