Abstract
Human thioredoxin-1 (TRX) is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys-. It has been demonstrated that systemic administration and transgenic overexpression of TRX ameliorate inflammation in various animal models, but its anti-inflammatory mechanism is not well characterized. We investigated the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX) in a murine irritant contact dermatitis (ICD) induced by croton oil. Topically applied rhTRX was distributed only in the skin tissues under both non-inflammatory and inflammatory conditions, and significantly suppressed the inflammatory response by inhibiting the production of cytokines and chemokines, such as TNF-α, Il-1β, IL-6, CXCL-1, and MCP-1. In an in vitro study, rhTRX also significantly inhibited the formation of cytokines and chemokines produced by keratinocytes after exposure to croton oil and phorbol 12-myristate 13-acetate. These results indicate that TRX prevents skin inflammation via the inhibition of local formation of inflammatory cytokines and chemokines. As a promising new approach, local application of TRX may be useful for the treatment of various skin and mucosal inflammatory disorders.
Highlights
Thioredoxin-1 (TRX), a small (12-kDa) protein with a highly conserved redox-active dithiol/disulfide in the active site sequence Cys32-Gly-Pro-Cys35, plays a variety of redox-related roles in essentially all organisms on the earth ranging from Escherichia coli to humans [1]
In order to examine the effect of topically applied recombinant human thioredoxin (rhTRX) on irritant contact dermatitis (ICD), the mice were divided into five groups: [1] a group of mice received rhTRX 2 h before croton oil application, [2] a group of mice received bovine serum albumin (BSA) 2 h before croton oil application, [3] a group of mice received rhTRX treatment immediately after croton oil application, [4] a group of mice received BSA immediately after croton oil treatment, [5] a group of mice received heat-inactivated rhTRX immediately after croton oil treatment
The results showed that the average number of infiltrating neutrophils and the dilatation of the capillary blood vessels were significantly decreased in the rhTRX treated group, compared to BSA treated group (∗ ∗ ∗P < 0.001, ∗ ∗ ∗P < 0.001) (Figure 1C)
Summary
Thioredoxin-1 (TRX), a small (12-kDa) protein with a highly conserved redox-active dithiol/disulfide in the active site sequence Cys32-Gly-Pro-Cys, plays a variety of redox-related roles in essentially all organisms on the earth ranging from Escherichia coli to humans [1]. In addition to its anti-oxidant properties, TRX has a crucial role in the redox regulation of cellular signaling and activation. TRX is involved in various redox-dependent cellular processes, such as gene expression, signal transduction, cell growth, and apoptosis, interacting with various kinds of target molecules. Transgenic overexpression of TRX and the systemic administration of recombinant human thioredoxin (rhTRX) are effective in a wide variety of inflammatory disease models, such as viral pneumonia, acute lung injury, pancreatitis, myocarditis, chronic obstructive pulmonary diseases, and indomethacin-induced gastric injury [4,5,6,7,8,9]
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