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URL: https://pubmed.ncbi.nlm.nih.gov/12771994/

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

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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 long-term tumour growth following PDT using Photofrin((R)) 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((R)) PDT. They also lay the mechanistic groundwork for further ongoing studies that attempt to optimise PDT through the modulation of the critical inflammatory mediators.

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Figures

👁 Figure 1
Figure 1
HPPH-PDT enhances neutrophil infiltration into the treated tumour. Animals were treated with 0.6 μmol kg−1 HPPH, followed 24 h later by 100 J cm−2 of 665 nm light. Tumours were harvested at various times post-PDT and the infiltrating cell populations were analysed by flow cytometry as described in Materials and Methods. Samples were collected from control animals (no treatment, HPPH alone) at 6 h ‘post-PDT’. Results are reported as the percentage of total cells present in the tumour that are CD45+ and Gr-1+. A minimum of three mice were analysed at each time point. Error bars represent the s.e.
👁 Figure 2
Figure 2
Induction of MIP-2 and KC following PDT. Animals were treated with PDT as described in Figure 1. Tumours and sera were collected from treated animals at various times post-PDT. Tumours and sera were collected from control animals (no treatment, HPPH alone) at 6 h ‘post-PDT’. The total amount of protein per sample was determined using the Bio-Rad protein assay. KC and MIP-2 levels were determined by ELISA and are reported as (A) pg μg−1 of total protein or (B) fold induction where chemokine expression is reported in relation to the expression found in tumours treated with HPPH alone. A minimum of three mice were analysed at each time point. Error bars represent the s.e. MIP-2 👁 formula image
; KC 👁 formula image
👁 Figure 3
Figure 3
Induction of local and systemic IL-6 by PDT. Samples were collected from control animals (no treatment, HPPH alone) at 6 h ‘post-PDT’. The total amount of protein per tumour was determined using the Bio-Rad protein assay. (A) IL-6 levels were determined by ELISA and are reported as either pg μg−1 of total protein (tumour) or pg ml−1 serum. A minimum of three mice were analysed at each time point. Error bars represent the s.e. Tumour IL-6 👁 formula image
; serum IL-6 👁 formula image
. (B) EMT6 tumour-bearing mice were subjected to HPPH treatment. At 0 h, one group of five mice was exposed to light (135 J cm−2) (filled symbols), and another group of five mice was kept in the dark (control, open symbols). Every 24 h, a blood sample was collected for each mouse and the serum level of HP was determined by immunoelectrophoresis. The values were calculated in mg ml−1 and the HP concentration for each mouse and bleeding was reproduced.
👁 Figure 4
Figure 4
HPPH-PDT enhances adhesion molecule expression and neutrophil adhesion in tumour microvessels. Animals were treated as in Figure 1 for the indicated time periods and tumour cryosections were either stained for vascular adhesion molecule expression using specific mAb (A) or evaluated for the ability to support adhesion of neutrophils under mechanical shear (B). In (A), arrows denote tumour vessels; note that fluorescence was not detected in tumour vessels stained with isotype-matched control Ab (left panels) or in tumours that were not treated with light (i.e. no PDT, right panels). In contrast, E-selectin and ICAM-1 were highly expressed on tumour vessels following HPPH-PDT treatment. Data in (B) are the mean +s.d. of triplicate samples and are representative of three independent experiments. The differences between adhesion in untreated contralateral tumours and PDT-treated tumours were significant, P<0.005 (*), P<0.0005 (**) by unpaired two-tailed Student's t-test.
👁 Figure 5
Figure 5
(A) HPPH-PDT stimulates E-selectin-dependent adhesion of neutrophils to tumour microvessels. Animals were treated with HPPH for 6 h and separated into two groups: (1) the drug only group did not receive PDT treatment and (2) in the second group, tumours were treated with PDT, while contralateral tumours were not treated with light. Neutrophil adhesion to tumour microvessels was evaluated under mechanical shear in tumour cryosections in the presence of isotype-matched negative control Ab or function-blocking mAb specific for E-selectin (10 μg ml−1). Data are the mean ±s.d. of triplicate samples and are representative of three independent experiments. The difference between adhesion in untreated contralateral tumours and PDT-treated tumours was significant, P < 0.00035 (*) by unpaired two-tailed Student's t-test. (B) Inhibition of MIP-2 and E-Selectin expression following PDT diminishes PDT-induced neutrophil infiltration into EMT6 tumours. Tumour-bearing animals were treated with PDT as described under Figure 1. Anti-MIP-2, anti-E-selectin, anti-IL-6, anti-GR-1, rat IgG (isotype control for anti-MIP-2 and anti-E-selectin) or goat IgG (isotype control for anti-IL-6 and anti-GR-1) were administered immediately after PDT. Tumours were isolated 24 h post-PDT and the infiltrating cell populations were determined by flow cytometry. The dashed line indicates the level of neutrophils found in control tumours. Mean values from three animals of the percentage of total cells that are CD45+ and GR-1+ are shown. Error bars represent the s.e.m.

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