Radiation-induced alterations in cytokine production by skin cells
2007; Elsevier BV; Volume: 35; Issue: 4 Linguagem: Inglês
10.1016/j.exphem.2007.01.017
ISSN1873-2399
AutoresKerstin Müller, Viktor Meineke,
Tópico(s)Fibroblast Growth Factor Research
ResumoIonizing radiation exposure of skin results in a cutaneous radiation reaction comprising all pathophysiological reactions and clinical symptoms in irradiated skin. Biological responses of skin occur in a characteristic temporal pattern and mainly depend on radiation quality, dose rate, total dose, and cellular conditions. Immediately after irradiation, production of cytokines by skin cells is initiated and continues as a cascade during all stages of the cutaneous radiation syndrome leading to progressive late symptoms, the predominant of which is fibrosis. Cytokines are important signaling molecules mediating communicative interactions both locally between different cell types within dermal tissues and distantly between organs. Although during recent years much progress has been made in dissecting the complex cytokine network, the role of cytokines in the pathophysiology of the cutaneous radiation reaction is only beginning to be elucidated. Previous studies indicate that the major cytokines in the response of skin cells to ionizing radiation include IL (interleukin)-1, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and the chemokines IL-8 and eotaxin. In this paper, existing data on the radiation-induced modulation of cytokine expression by skin cells are reviewed. Ionizing radiation exposure of skin results in a cutaneous radiation reaction comprising all pathophysiological reactions and clinical symptoms in irradiated skin. Biological responses of skin occur in a characteristic temporal pattern and mainly depend on radiation quality, dose rate, total dose, and cellular conditions. Immediately after irradiation, production of cytokines by skin cells is initiated and continues as a cascade during all stages of the cutaneous radiation syndrome leading to progressive late symptoms, the predominant of which is fibrosis. Cytokines are important signaling molecules mediating communicative interactions both locally between different cell types within dermal tissues and distantly between organs. Although during recent years much progress has been made in dissecting the complex cytokine network, the role of cytokines in the pathophysiology of the cutaneous radiation reaction is only beginning to be elucidated. Previous studies indicate that the major cytokines in the response of skin cells to ionizing radiation include IL (interleukin)-1, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and the chemokines IL-8 and eotaxin. In this paper, existing data on the radiation-induced modulation of cytokine expression by skin cells are reviewed. The term cutaneous radiation reaction, also referred to as cutaneous radiation syndrome, describes the total of pathophysiological reactions and clinical symptoms induced in skin as a result of ionizing radiation exposure. Skin reactions occur in a characteristic temporal pattern consisting of prodomal erythema, manifestation stage, subacute stage, chronic stage, and late stage [1Peter R.U. Klinische Aspekte des kutanen Strahlensyndroms nach Strahlenunfällen—Erfahrungen von Goiania und Tschernobyl.Aktuel Dermatol. 1993; 19: 364-367Google Scholar, 2Peter R.U. The cutaneous radiation syndrome.in: MacVittie T.J. Weiss J.F. Browne D. Advances in the Treatment of Radiation Injuries. Elsevier, Oxford, UK1996: 237-241Google Scholar]. However, duration and severity of the individual phases, the degree of skin damage, and the ability of skin cells to recover from radiation damage mainly depend on radiation quality, dose rate, total dose, and cellular conditions [1Peter R.U. Klinische Aspekte des kutanen Strahlensyndroms nach Strahlenunfällen—Erfahrungen von Goiania und Tschernobyl.Aktuel Dermatol. 1993; 19: 364-367Google Scholar, 2Peter R.U. The cutaneous radiation syndrome.in: MacVittie T.J. Weiss J.F. Browne D. Advances in the Treatment of Radiation Injuries. Elsevier, Oxford, UK1996: 237-241Google Scholar, 3Goldschmidt H. Dermatologische Röntgentherapie und Radiokarzinogenese.Hautarzt. 1982; 33: 183-190PubMed Google Scholar]. Ionizing radiation may have an impact on virtually every single component of the cell. It not only affects the proliferative capacity of skin stem cells, but also modulates the communication between cells leading to skin damage and impaired cutaneous integrity. In the initial phase of the cutaneous radiation syndrome, a transient and inconsistent erythema may occur. In this early phase, a few hours after irradiation, a transcriptional activation of a cascade of cytokines is initiated. The cytokines released by irradiated cells bind to receptors on cells within the same tissue or on distant cells and stimulate them to generate a biological response [4Hallahan D.E. Radiation-mediated gene expression in the pathogenesis of the clinical radiation response.Semin Radiat Oncol. 1996; 6: 250-267Abstract Full Text PDF PubMed Scopus (36) Google Scholar]. Cytokines induce the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on keratinocytes and endothelial cells as well as vascular cell adhesion molecule (VCAM) and E-selectin on endothelial cells [5Behrends U. Peter R.U. Hintermeier-Knabe R. et al.Ionizing radiation induces human intercellular adhesion molecule-1 in vitro.J Invest Dermatol. 1994; 103: 726-730Crossref PubMed Scopus (89) Google Scholar, 6Müller K, Köhn FM, Port M, et al. Intercellular adhesion molecule-1: a consistent inflammatory marker of the cutaneous radiation reaction both in vitro and in vivo. Br J Dermatol. In press.Google Scholar, 7Heckmann M. Douwes K. Peter R. Degitz K. Vascular activation of adhesion molecule nmRNA and cell surface expression by ionizing radiation.Exp Cell Res. 1998; 238: 148-154Crossref PubMed Scopus (96) Google Scholar, 8Meineke V. Moede T. Gilbertz K.P. et al.Protein kinase inhibitors modulate time-dependent effects of UV and ionizing radiation on ICAM-1 expression on human hepatoma cells.Int J Radiat Biol. 2002; 78: 577-583Crossref PubMed Scopus (16) Google Scholar]. This activation pattern causes an increased vascular permeability, activation of inflammatory cells, and their transendothelial migration from the circulation into the inflamed tissue. The onset and intensity of the early erythema are determined by the radiation dose. This condition is dose-dependent and clinically asymptomatic as long as a balance between pro-inflammatory and anti-inflammatory processes exists. Up to now it has been commonly accepted to distinguish between different clinical stages of the cutaneous radiation reaction. Although new data from a retrospective analysis of clinical courses of the cutaneous radiation reaction in radiation victims suggest that a strict separation of these individual clinical stages in general may no longer be reasonable (Meineke et al., manuscript in preparation), this old classification still bears some didactic advantages with respect to the understanding of the pathophysiological sequence of the events occurring in radiation-exposed skin. According to this classification, within days to a few weeks, the manifestation stage may appear. This stage is characterized by intense reddening, blistering, and ulceration of the irradiated tissue. Tissue destruction, capillaritis and vasculitis of dermal venules and arterioles, and granulocyte infiltration result in the development of a complex wound [9Hopewell J.W. The skin: its structure and response to ionizing radiation.Int J Radiat Biol. 1990; 57: 751-773Crossref PubMed Scopus (263) Google Scholar]. As a consequence of these inflammatory reactions, considerable tissue damage gradually evolves. In the chronic stage of the cutaneous radiation syndrome, with a latency of 3 months to 2 years, epidermal keratosis, atrophy, telangiectasia, and fibrosis may occur. Fibrosis is progressive by nature. Its predominant characteristics are massive deposition of extracellular matrix and excessive fibroblast proliferation [9Hopewell J.W. The skin: its structure and response to ionizing radiation.Int J Radiat Biol. 1990; 57: 751-773Crossref PubMed Scopus (263) Google Scholar, 10Bentzen S.M. Thames H.D. Overgaard M. Latent-time estimations for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study.Radiother Oncol. 1989; 15: 267-274Abstract Full Text PDF PubMed Scopus (173) Google Scholar, 11Lefaix J.L. Daburon F. Diagnosis of acute localized irradiation lesions: A review of the French experimental experience.Health Phys. 1998; 75: 375-384Crossref PubMed Scopus (40) Google Scholar]. Taken together, cytokine expression is initiated immediately after irradiation and persists for months and possibly years, having an impact on all stages of the cutaneous radiation syndrome. This review will summarize the current knowledge on radiation-induced modulation of cytokine expression in skin cells. Cytokines are soluble polypeptides that are produced by a wide variety of cell types either constitutively or after induction. They are involved in virtually every aspect of immunity and inflammation, including development and functioning of the immune system, cell proliferation and differentiation, cellular recruitment and activation, and regulation of cellular interactions with extracellular matrix proteins. Cytokines mediate the communication both locally between cells and tissues and distantly between organs [12Nathan C. Sporn M. Cytokines in context.J Cell Biol. 1991; 113: 981-986Crossref PubMed Scopus (692) Google Scholar, 13Borish L.C. Steinke J.W. Cytokines and chemokines.J Allergy Clin Immunol. 2003; 111: S460-S475Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar]. They exert their functions in an autocrine, paracrine, or endocrine matter by binding to highly specific cell-surface receptors on target cells. Subsequently, intracellular signaling cascades are initiated that cause changes in gene expression. The cellular response is influenced by the differentiation status, the configuration and distribution of cytokine receptors, the mechanisms of cell attachment to the extracellular matrix, and the current status of cell signaling. Cytokines exhibit a few important characteristics, one of which is pleiotropy, which means that the same cytokine may have different activities on different cell types. Depending on the situation, different cytokines may have the same activity, a term called redundancy. Cytokines often act together and amplify the effects of one another. This synergy is often a prerequisite to express optimal functions. Numerous cytokines have both pro-inflammatory and anti-inflammatory potential [12Nathan C. Sporn M. Cytokines in context.J Cell Biol. 1991; 113: 981-986Crossref PubMed Scopus (692) Google Scholar, 13Borish L.C. Steinke J.W. Cytokines and chemokines.J Allergy Clin Immunol. 2003; 111: S460-S475Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar]. Based on the fact that cytokines often affect the synthesis of other cytokines, inhibiting or assisting one cytokine pathway may influence other cytokine pathways, possibly leading to unpredictable implications [14Schooltink H. Rose-John S. Cytokines as therapeutic drugs.J Interferon Cytokine Res. 2002; 22: 505-516Crossref PubMed Scopus (43) Google Scholar]. Although during recent years much progress has been made in dissecting the complex cytokine network, the role of cytokines in the pathophysiology of the cutaneous radiation reaction is only beginning to be elucidated. Cytokines are of utmost importance for signaling between cells and tissues and there is increasing evidence that they constitute a humoral component of the response of cells and tissues to radiation exposure [15Langberg C.W. Hauer-Jensen M. Sung C.C. Kane C.J. Expression of fibrogenic cytokines in rat small intestine after fractionated irradiation.Radiother Oncol. 1994; 32: 29-36Abstract Full Text PDF PubMed Scopus (130) Google Scholar, 16Rubin P. Johnston C.J. Williams J.P. McDonald S. Finkelstein J.N. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis.Int J Radiat Oncol Biol Phys. 1995; 33: 99-109Abstract Full Text PDF PubMed Scopus (556) Google Scholar]. Recently, a new concept has emerged regarding the induction of radiation damages. It suggests that a cascade of cytokines is initiated immediately after irradiation and during the clinically silent stage, persists for long periods of time, and leads to the development of late radiation damage [16Rubin P. Johnston C.J. Williams J.P. McDonald S. Finkelstein J.N. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis.Int J Radiat Oncol Biol Phys. 1995; 33: 99-109Abstract Full Text PDF PubMed Scopus (556) Google Scholar]. Previous studies indicate that the major cytokines in the response of skin cells to ionizing radiation include interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. In addition, skin cells have the potential to release granulocyte-macrophage colony-stimulating factor (GM-CSF) and chemotactic cytokines such as IL-8 and eotaxin following ionizing radiation. IL-1 is one of the few cytokines that has been demonstrated to be directly induced by ionizing radiation [5Behrends U. Peter R.U. Hintermeier-Knabe R. et al.Ionizing radiation induces human intercellular adhesion molecule-1 in vitro.J Invest Dermatol. 1994; 103: 726-730Crossref PubMed Scopus (89) Google Scholar, 17Liu W. Ding I. Chen K. et al.Interleukin 1β (IL1B) signaling is a critical component of radiation-induced skin fibrosis.Radiat Res. 2006; 165: 181-191Crossref PubMed Scopus (73) Google Scholar, 18Hirota S. Tsujino K. Oshitani T. et al.Subcutaneous fibrosis after whole neck irradiation.Int J Radiat Oncol Biol Phys. 2002; 52: 937-943Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. This pro-inflammatory cytokine exists in two forms, IL-1α and IL-1β, which have similar biological activities and both interact with the same receptor. IL-1 is of utmost importance in the acute-phase inflammatory response and the regulation of hematopoiesis. It is able to activate T lymphocytes, to enhance proliferation of B cells, and to stimulate adherence of leukocytes to the endothelium by upregulation of adhesion molecule expression. Some of the most relevant functions of IL-1 with respect to late effects of ionizing radiation exposure are the stimulation of proliferation of keratinocytes and fibroblasts and the induction of matrix metalloproteases (MMP) and collagen synthesis [19Romero L.I. Zhang D.N. Herron G.S. Karasek M.A. Interleukin-1 induces major phenotypic changes in human skin microvascular endothelial cells.J Cell Physiol. 1997; 173: 84-92Crossref PubMed Scopus (66) Google Scholar, 20Lambert C.A. Lapiere C.M. Nusgens B.V. 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The synthesis of IL-1 is induced by a variety of stimuli including endotoxin, other cytokines, and microbial and viral antigens, as well as ionizing radiation. In skin from C57BL/6 mice locally irradiated with a single dose of 30 Gy, keratinocytes have been identified as the major cell type responsible for production of IL-1. It has been demonstrated in murine skin that IL-1β protein levels increased immediately after ionizing radiation and remained chronically elevated, whereas IL-1α protein levels increased slowly with time after irradiation [17Liu W. Ding I. Chen K. et al.Interleukin 1β (IL1B) signaling is a critical component of radiation-induced skin fibrosis.Radiat Res. 2006; 165: 181-191Crossref PubMed Scopus (73) Google Scholar]. Parallel studies from this group on primary human keratinocytes revealed that ionizing radiation with 10 Gy caused an induction of IL-1 at both the mRNA and protein level [17Liu W. Ding I. 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The most important source of IL-6 is mononuclear phagocytic cells, but IL-6 is also produced by fibroblasts, keratinocytes, endothelial cells, T and B lymphocytes, hepatocytes, and bone marrow cells [30Van Snick J. Interleukin-6: an overview.Annu Rev Immunol. 1990; 8: 253-278Crossref PubMed Google Scholar]. In previous studies, ionizing radiation has been shown to modulate the expression of IL-6 in different human cell types such as fibroblasts, keratinocytes, and epithelial cells [33Tabata C. Kubo H. Tabata R. et al.All-trans retinoic acid modulates radiation-induced proliferation of lung fibroblasts via IL-6/IL-6R system.Am J Physiol Lung Cell Mol Physiol. 2006; 290: L597-L606Crossref PubMed Scopus (47) Google Scholar, 34Brach M.A. Gruss H.J. Kaisho T. Asano Y. Hirano T. Herrmann F. Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.J Biol Chem. 1993; 268: 8466-8472Abstract Full Text PDF PubMed Google Scholar, 35Petit-Frere C. Capulas E. Lyon D.A. et al.Apoptosis and cytokine release induced by ionizing or ultraviolet B radiation in primary and immortalized human keratinocytes.Carcinogenesis. 2000; 21: 1087-1095Crossref PubMed Google Scholar, 36Beetz A. Messer G. Oppel T. van Beuningen D. Peter R.U. Kind P. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.Int J Radiat Biol. 1997; 72: 33-43Crossref PubMed Scopus (68) Google Scholar]. Human embryonic lung fibroblasts FH109 have been reported to respond to a single dose of 5 Gy with an upregulation of IL-6 protein expression levels as early as 6 hours after irradiation [34Brach M.A. Gruss H.J. Kaisho T. Asano Y. Hirano T. Herrmann F. Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.J Biol Chem. 1993; 268: 8466-8472Abstract Full Text PDF PubMed Google Scholar]. The elevated IL-6 levels in the supernatant of irradiated fibroblasts were reflected by increased IL-6 mRNA expression levels [34Brach M.A. Gruss H.J. Kaisho T. Asano Y. Hirano T. Herrmann F. Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.J Biol Chem. 1993; 268: 8466-8472Abstract Full Text PDF PubMed Google Scholar]. It is well established that the IL-6 promoter contains a large number of DNA binding sites for inducible transcription factors including nuclear factor (NF)-κB, activator protein (AP)-1, AP-2, NF-IL-6, and cAMP-responsive element binding protein (CREB) [37Libermann T.A. Baltimore D. 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Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.J Biol Chem. 1993; 268: 8466-8472Abstract Full Text PDF PubMed Google Scholar]. The authors have shown that both activation of transcription factors and induction of IL-6 mRNA expression occur independently of de novo protein synthesis, indicating that ionizing radiation causes posttranslational modifications of preexisting NF-κB and AP-1 proteins [34Brach M.A. Gruss H.J. Kaisho T. Asano Y. Hirano T. Herrmann F. Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.J Biol Chem. 1993; 268: 8466-8472Abstract Full Text PDF PubMed Google Scholar]. Increased IL-6 protein levels following ionizing radiation have also been observed in HaCaT and HeLa cells which was accompanied by accumulation of IL-6 transcripts [35Petit-Frere C. Capulas E. Lyon D.A. et al.Apoptosis and cytokine release induced by ionizing or ultraviolet B radiation in primary and immortalized human keratinocytes.Carcinogenesis. 2000; 21: 1087-1095Crossref PubMed Google Scholar, 36Beetz A. Messer G. Oppel T. van Beuningen D. Peter R.U. Kind P. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.Int J Radiat Biol. 1997; 72: 33-43Crossref PubMed Scopus (68) Google Scholar]. In HeLa cells, IL-6 expression has been demonstrated to be dose-dependently increased up to a single dose of 20 Gy [36Beetz A. Messer G. Oppel T. van Beuningen D. Peter R.U. Kind P. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.Int J Radiat Biol. 1997; 72: 33-43Crossref PubMed Scopus (68) Google Scholar]. The radiation-induced upregulation of IL-6 expression could be inhibited in a dose-dependent manner by pretreatment of epithelial cells with corticosteroid derivatives hydrocortisone, dexamethasone, or mometasone furoate prior to ionizing radiation [36Beetz A. Messer G. Oppel T. van Beuningen D. Peter R.U. Kind P. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.Int J Radiat Biol. 1997; 72: 33-43Crossref PubMed Scopus (68) Google Scholar]. The IL-6 promoter contains at least four glucocorticoid-responsive elements (GRE), which bind complexes of corticosteroids with intracellular receptors and are located in positions of transcription factor binding motifs. It has been speculated that the bound corticosteroid receptor complexes inhibit the recognition of transcription factors involved in activation of the IL-6 promoter [43Ray A. LaForge K.S. Sehgal P.B. On the mechanism for efficient repression of the interleuki
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