title: 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 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.
authors.affiliation: PDT Center, Roswell Park Cancer Institute, Elm and Carlton St, Buffalo, NY 14263, USA.
authors.forename: S O
authors.initials: SO
authors.lastname: Gollnick
authors.forename: S S
authors.initials: SS
authors.lastname: Evans
authors.forename: H
authors.initials: H
authors.lastname: Baumann
authors.forename: B
authors.initials: B
authors.lastname: Owczarczak
authors.forename: P
authors.initials: P
authors.lastname: Maier
authors.forename: L
authors.initials: L
authors.lastname: Vaughan
authors.forename: W C
authors.initials: WC
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Unger
authors.forename: B W
authors.initials: BW
authors.lastname: Henderson
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism / Q000502:physiology*; D019743:Chemokines, CXC / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016207:Cytokines / Q000502:physiology*; D019040:E-Selectin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D019040:E-Selectin; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D015846:Monokines; D017319:Photosensitizing Agents; D018799:Intercellular Adhesion Molecule-1; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a