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Photodynamic Therapy Induces Expression of Interleukin 6 by Activation of AP-1 but not NF-B DNA Binding¹

Department of Dermatology [G. K., G. M., G. P., P. K.] and Institute for Anesthesiology [A. G.], Ludwig-Maximilians University of Munich, 80337 Munich, Germany

Inducibility and regulation of the pleiotropic cytokine interleukin 6 (IL-6) upon photodynamic therapy (PDT) was studied in the epithelial cell line HeLa. Photofrin-mediated photosensitization resulted in a rapid and dose-dependent induction of IL-6 mRNA production. Maximal levels were reached after 4 h and had decreased to baseline levels after 24 h. This photochemical induction of IL-6 transcription was followed by a strong secretion of IL-6 protein. In comparison to stimulation by 12-O-tetradecanoylphorbol-13-acetate, the kinetics of IL-6 mRNA and protein synthesis after PDT were delayed, although the maximal amounts of secreted IL-6 protein were comparable. As compared to UV irradiation, on the other hand, PDT-induced IL-6 protein levels were 2- to 10-fold higher and were detectable 4 h earlier. Several potentially relevant regulatory DNA elements of the IL-6 promoter were analyzed by gel retardation assays for PDT-induced protein binding. Interestingly, increased AP-1 DNA binding was detected only at the distal AP-1-specific motif and not at the proximal site, differing in 1 bp. Binding of c-Fos-containing AP-1 heterodimers to the specific motif was up-regulated 30 min after PDT, reaching maximal activity at 4 h. This PDT-induced AP-1 activation was independent from protein kinase C activity. Photosensitization did not induce increased binding at the well-characterized NF-B element, nor at the multiple cytokine- and second messenger-responsive element of the IL-6 promoter. By analyzing the molecular mechanisms of IL-6 up-regulation upon PDT, we provide evidence for regulatory differences compared to UV light, ionizing irradiation, or stimulation by phorbol ester. Furthermore, this study suggests that the "proinflammatory" cytokine IL-6 might be involved in the inflammatory reaction and subsequent immunological antitumor responses.

¹ This investigation was supported by a Grant 0706903A5 from the Bundesministerium für Forschung und Technologie (to A. G.) and the Dr. Bodo Sponholz Stiftung (Frankfurt, Germany) and is part of the doctoral thesis of G. K.

² To whom requests for reprints should be addressed, at Dermatologische Klinik der Ludwig-Maximilians, University of Munich, Frauenlobstr. 9-11, 80337 Munich, Germany.

³ Present address: Institute for Anesthesiology, Ludwig-Maximilians University of Munich, Marchioninistr. 15, 81377 Munich, Germany.

Received 1/17/95. Accepted 4/ 5/95.

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