Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus

Abstract

OBJECTIVE: To investigate the role of the novel cytokine high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of cutaneous lupus erythematosus (CLE). METHODS: Punch biopsy specimens of lesional and unaffected skin from 10 patients with CLE and 3 healthy control subjects were investigated. Immunohistochemical staining for HMGB-1, tumor necrosis factor alpha (TNFalpha), and interleukin-1beta (IL-1beta) was performed on consecutive sections. Analysis of single-nucleotide polymorphisms of -308 TNF was performed on DNA extracted from peripheral blood mononuclear cells. RESULTS: An altered expression of HMGB-1 was observed both in the epidermis and in the dermal infiltrates of lesional skin. Expression of HMGB-1 in the epidermis and dermis was increased (P < 0.01 and P < 0.001, respectively, versus unaffected skin), and translocation to the cytoplasm as well as the extracellular presence of secreted HMGB-1 were found. Increased levels of TNFalpha and IL-1beta were also observed in the dermal infiltrates of lesional skin (P < 0.01 and P < 0.05, respectively, versus unaffected skin). The carrier frequency of the -308A TNF polymorphism was 80% in patients with subacute CLE, but this was not related to higher expression of TNFalpha in biopsy specimens from the CLE group. CONCLUSION: The high amount of extracellular HMGB-1 observed in skin lesions indicates that HMGB-1 is involved in the inflammatory process of CLE. TNFalpha and IL-1beta may form a proinflammatory loop with HMGB-1, since they can induce the release of each other. The extracellular HMGB-1 observed by immunostaining of the epidermis indicates that keratinocytes may be an as yet unrecognized source of secreted HMGB-1, underscoring the role of the target organ in the rheumatoid autoimmune inflammatory process.