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 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-alpha (IL-6Ralpha) (sIL-6Ralpha) 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-6Ralpha 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.
Wei
L-H
LH
Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. weilh1966@gmail.com
Baumann
H
H
Tracy
E
E
Wang
Y
Y
Hutson
A
A
Rose-John
S
S
Henderson
B W
BW
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000378:metabolism
D017077:Culture Media, Conditioned; D019927:Cyclin E; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C113250:interleukin-6 receptor alpha; D002734:Chlorophyll; D050760:Cyclin-Dependent Kinase Inhibitor p27; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases