Antioxidants attenuate anthralin-induced skin inflammation in BALB/c mice: role of specific proinflammatory cytokines

Abstract

Anthralin is the most common therapeutic agent among a small number of pro-oxidant, 9-anthrones effective in the topical treatment of psoriasis. However, the usefulness of this drug is diminished by toxic side effects, including skin irritation and inflammation. The activities of anthralin are believed to be mediated by the generation of reactive oxygen intermediates and anthrone radicals produced in the skin. In this study, the dermal inflammatory response to anthralin was determined using a mouse ear swelling test. Maximum ear swelling induced by anthralin coincided with the elevation of cytokine mRNA expression in the skin, including interleukin-6, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-2, and tumor necrosis factor ␣ at 24 h post challenge. The role of free radical generation in ear swelling and cytokine modulation were examined by systemic administration of cell permeable and impermeable antioxidants before anthralin challenge. Superoxide dismutase and ␣-tocopherol acetate, but not the glutathione precursor N-acetyl cysteine, were effective inhibitors of anthralininduced ear swelling and cytokine elevation. Maximum inflammatory cell infiltration occurred 72-96 h post anthralin challenge and was also reduced by antioxidants. These data suggest that oxidative stress, generated at the site of anthralin treatment, alters the expression of dermal chemokines and other cytokines resulting in the recruitment of inflammatory cells. Systemic antioxidant administration may provide opportunities for therapeutic intervention against anthralin-associated toxicities.

Thioredoxin Ameliorates Cutaneous Inflammation by Regulating the Epithelial Production and Release of Pro-Inflammatory Cytokines

“…Accumulating evidence indicates that oxidative stress is associated with inflammation, and thiol anti-oxidants, especially glutathione, have often been thought of as possible anti-inflammatory mediator (26). Indeed, oxidative stress plays an important role in many inflammatory diseases, including ICD (27–29). A molecular mechanism for this association was first provided in 1991, with the finding that H 2 O 2 activates the transcription factor NF-κB, which is involved in the production of many inflammatory cytokines, while thiol anti-oxidants inhibit its activation (30).…”

Gene expression in rat skin induced by irritating chemicals

“…Bernard and coworkers [21] compared gene expression profiles using a customized cDNA microarray system in keratinocytes, reconstituted epidermis, and human skin and investigated the effect of retinoid treatments on gene expression. Other studies have looked at smaller numbers of specific gene responses to a variety of treatments in keratinocytes [22][23][24], cultured skin [20,25], mouse skin [26], and human skin [27].…”

Current Status and Recent Developments in Anthracenone Antipsoriatics

“…In addition to directly damaging cellular components of the skin, oxygen radicals can act as chemical messengers [58,59] to influence signal transduction pathways or regulate gene expression of inflammatory cytokines via activation of transcription factors [60][61][62][63]. In support of this, recent studies with anthralin have shown that oxygen radicals generated from anthralin are responsible for the induction of proinflammatory cytokines such as IL-6, IL-8, and TNF-α, resulting in the recruitment of inflammatory cells [64,65]. Anthralin was also described as a novel inducer of the transcription factor NF-κB [66].…”