Mechanistic insights into topical tacrolimus for the treatment of atopic dermatitis

    loading  Checking for direct PDF access through Ovid

Excerpt

Tacrolimus, a calcineurin inhibitor, was discovered in the biomolecules produced by the actinomycete strain Streptomyces tsukubaensis in 1984. Tacrolimus mainly acts on T cells by inhibiting the activation of both the T helper (Th) 1 and Th2 phenotypes.1 The production of Th1 [interferon‐γ (IFN‐γ) and interleukin (IL)‐2] and Th2 (IL‐4 and IL‐5) cytokines is potently inhibited by tacrolimus.1 Tacrolimus also suppresses histamine release from mast cells.2 Since its first launch in Japan in 1999, topical tacrolimus is currently approved and available in over 75 countries for the treatment of atopic dermatitis (AD). Topical tacrolimus has expanded the treatment options for AD, as it can be used on patients who are unresponsive to topical steroids and for patients who cannot receive steroids due to side effects.
The cardinal complaints of AD include pruritus, chronic inflammation, and dry skin with abnormal skin barrier function, which progress chronically with remissions and exacerbations.4 A Th2 cytokine‐mediated allergic response is involved in its onset and progression, and scratching due to severe pruritus of the lesion destroys skin barrier function, resulting in a vicious cycle (the itch‐scratch cycle) that further exacerbates symptoms.5 The current disease pathogenesis is supported by recent genomewide association studies (GWAS). Results of GWAS conducted in Europe, China, and Japan have suggested that gene clusters associated with barrier function and Th2 inflammation function as the disease‐susceptibility genes of AD.6 Moreover, the condition of patients with AD is significantly improved by administration of anti‐IL‐4 receptor α antibodies.7 Notably, IL‐31, which is preferentially produced by Th2 cells, induces the itch sensation. The pruritus of AD is significantly suppressed by anti‐IL‐31 receptor A antibody administration.8
More than 15 years have passed since the launch of tacrolimus ointment, and many new insights regarding the control of AD progression have come to light. In this review, we summarize recent mechanistic findings of tacrolimus, including suppression of itching, inhibition of allergic inflammation, and improvement in skin barrier function. The advancements in our understanding of the pathomechanisms of AD warrant an investigation of new potential uses of topical tacrolimus in its treatment.

Related Topics

    loading  Loading Related Articles