Mitogen-activated protein kinases and their inhibitors: Friend or foe in fighting psoriasis?

The pathogenesis of psoriasis, which has epidermal and immune system components, remains to be deciphered fully. The epidermal component includes aberrant differentiation and hyper-proliferation of epidermal keratinocytes, leading to a disrupted skin barrier characterized by an altered stratum corneum. The immune system component includes T-lymphocyte-mediated autoimmune reactions, increased pro-inflammatory cytokine production, and localization of these cytokines in psoriasiform lesions. The most common treatments currently used include photo-therapies, topical steroids, oral retinoids, immunosuppressive agents such as methotrexate or cyclosporine, and newer biological agents that block cytokine or cellular immune factors. An emerging theory from immunologists suggests that kinases downstream of MAPK family members p38 and ERK1/2 are responsible for the increased cytokine levels in the epidermis of psoriatic skin, and potent inhibitors of p38 and ERK1/2 have been developed by pharmaceutical companies aimed at suppression of inflammation in psoriasis patients. However, MAPK components and pathways are dynamic signal transduction systems that are essential to epithelial homeostasis. In the epidermal keratinocytes, p38 plays an important role in regulating cell growth and differentiation, as well as in stress response defense mechanisms. Systemic or topical application of p38 inhibitors would suppress cytokine release from lymphocytes, but may also simultaneously attenuate the regulatory and defensive role of p38 in the keratinocytes. Therefore, treatment with such pharmacological inhibitors has the potential for adverse consequences for patients (and the pharmaceutical companies).