Role of cytokines in photodynamic therapy-induced local and systemic inflammation

Abstract

Photodynamic therapy (PDT) of tumour results in the rapid induction of an inflammatory response that is considered important for the activation of antitumour immunity, but may be detrimental if excessive. The response is characterised by the infiltration of leucocytes, predominantly neutrophils, into the treated tumour. Several preclinical studies have suggested that suppression of longterm tumour growth following PDT using Photofrin s is dependent upon the presence of neutrophils. The inflammatory pathways leading to the PDT-induced neutrophil migration into the treated tumour are unknown. In the following study, we examined, in mice, the ability of PDT using the second-generation photosensitiser 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) to induce proinflammatory cytokines and chemokines, as well as adhesion molecules, known to be involved in neutrophil migration. We also examined the role that these mediators play in PDT-induced neutrophil migration. Our studies show that HPPH-PDT induced neutrophil migration into the treated tumour, which was associated with a transient, local increase in the expression of the chemokines macrophage inflammatory protein (MIP)-2 and KC. A similar increase was detected in functional expression of adhesion molecules, that is, E-selectin and intracellular adhesion molecule (ICAM)-1, and both local and systemic expression of interleukin (IL)-6 was detected. The kinetics of neutrophil immigration mirrored those observed for the enhanced production of chemokines, IL-6 and adhesion molecules. Subsequent studies showed that PDT-induced neutrophil recruitment is dependent upon the presence of MIP-2 and E-selectin, but not on IL-6 or KC. These results demonstrate a PDT-induced inflammatory response similar to, but less severe than obtained with Photofrin s PDT. They also lay the mechanistic groundwork for further ongoing studies that attempt to optimise PDT through the modulation of the critical inflammatory mediators.

Intracellular signaling mechanisms in photodynamic therapy

“…The mRNA for IL-6 was also changed by PDT with Photofrin in EMT6 mammary tumor cells in culture and in vivo, and a concomitant up-regulation in the interleukin protein levels was also observed in the latter model [174]. An enhanced expression of IL-6 in EMT6 tumors and an increase in the circulatory levels of IL-6 were also observed in in vivo studies, using the sensitizer HPPH [266]. The up-regulation in the IL-6 levels contrasts with the observed impairment of the response of hypopharyngeal carcinoma FaDu cells and of cultured human pulmonary fibroblasts to IL-6-type cytokines (IL-6, LIF and oncostatin M), observed after photosensitization with ALA or Photofrin [192] (see above).…”

“…The up-regulation in the IL-6 levels contrasts with the observed impairment of the response of hypopharyngeal carcinoma FaDu cells and of cultured human pulmonary fibroblasts to IL-6-type cytokines (IL-6, LIF and oncostatin M), observed after photosensitization with ALA or Photofrin [192] (see above). This may account for the lack of effect of IL-6 on neutrophil infiltration of EMT6 tumors, when HPPH was used as a sensitizer [266], but contrasts with the role of the cytokine on the induction of systemic neutrophilia in Photofrin-PDT [267,270].…”

“…Also, the upregulation in E-selectin in the tumor microvasculature increased the adhesion of EMT6 microvessels. Although there was also an increase in the neutrophil attractant chemokine KC, it had no effect on the recruitment of neutrophils [266]. Once at the tumor site, neutrophils may cause direct tumor cell destruction, may recruit leucocytes and lymphocytes by secreting chemokines/cytokines and may be implicated in tumor rejection in T-cell-dependent reactions [269].…”

Photodynamic therapy and anti-tumour immunity

“…These include IL6 in particular and macrophage inflammatory protein 1 (MIP1) and MIP2 (REF. 63). Increased levels of IL1β, IL6, IL8 and IL10 were detected in patients after surgery and PDT for mesothelioma64.…”

Non-Invasive Treatment of Extensive Eyelid Cancerous Lesion by Photodynamic Therapy: A Case Report

“…PDT results in photochemical and photo-biological processes which cause irreversible photodamage to the treated tissues [15]. The inflammatory process occurring after seven days following the first PDT session is observed in Figure 1, panel B, which is characterized by enhanced expression of pro-inflammatory cytokines and leukocyte infiltration [16]. Many studies on the efficacy of PDT on BCC have been published [4,17,18].…”