Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling

Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumou...

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Vydáno v:	British journal of cancer Ročník 97; číslo 11; s. 1513 - 1522
Hlavní autoři:	Wei, L-H, Baumann, H, Tracy, E, Wang, Y, Hutson, A, Rose-John, S, Henderson, B W
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 03.12.2007 Nature Publishing Group
Témata:	Animals Biological and medical sciences Biomedical and Life Sciences Biomedicine Blotting, Western Cancer Research cdc25 Phosphatases - metabolism Cell cycle Cell Cycle - drug effects Cell Cycle - physiology Cell growth Cell Line, Tumor Cell Proliferation - drug effects Chlorophyll - analogs & derivatives Chlorophyll - pharmacology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Culture Media, Conditioned - pharmacology Cyclin E - metabolism Cyclin-Dependent Kinase 2 - metabolism Cyclin-Dependent Kinase Inhibitor p27 - metabolism Cytokines Dose-Response Relationship, Drug Drug Resistance Epidemiology HeLa Cells Humans Inflammation Interleukin-6 - metabolism Interleukin-6 - pharmacology Interleukin-6 - physiology Macrophages - drug effects Macrophages - metabolism Medical research Medical sciences Mice Mice, Inbred BALB C Molecular Medicine Oncology Penicillin Photochemotherapy Photodynamic therapy Receptors, Interleukin-6 - metabolism Signal Transduction - physiology STAT3 Transcription Factor - metabolism Thoracic surgery Translational Therapeutics Tumors United States > US soluble interleukin-6 receptor cell cycle photodynamic therapy interleukin-6 Interleukin 6 Signal transduction Cancerology Photodynamic therapy Cell therapy Treatment Interleukin 6 receptor Cytokine Cell cycle Soluble form
ISSN:	0007-0920, 1532-1827
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Popis
Shrnutí:	Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumour cells are subject to regulation by IL-6 and whether this regulation could contribute to tumour control by PDT. We demonstrate in epithelial tumour cells that while the action of IL-6 cytokines through their membrane receptors is attenuated, regulation by IL-6 via trans-signalling is established. Soluble interleukin-6 receptor- α (IL-6R α ) (sIL-6R α ) and IL-6 were released by leucocytes in the presence of conditioned medium from PDT-treated tumour cells. Cells that had lost their membrane receptor IL-6R α due to PDT responded to treatment with the IL-6R–IL-6 complex (Hyper-IL-6) with activation of signal transducers and activator of transcription (STAT3) and ERK. Photodynamic therapy-treated cells, which were maintained during post-PDT recovery in presence of IL-6 or Hyper-IL-6, showed an enhanced suppression of proliferation. Cytokine-dependent inhibition of proliferation correlated with a decrease in cyclin E, CDK2 and Cdc25A, and enhancement of p27kip1 and hypophosphorylated Rb. The IL-6 trans-signalling-mediated attenuation of cell proliferation was also effective in vivo detectable by an improved Colon26 tumour cure by PDT combined with Hyper-IL-6 treatment. Prevention of IL-6 trans-signalling using soluble gp130 reduced curability. The data suggest that the post-PDT tumour milieu contains the necessary components to establish effective IL-6 trans-signalling, thus providing a means for more effective tumour control.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0007-0920 1532-1827
DOI:	10.1038/sj.bjc.6604073