Methotrexate Therapy of Psoriasis: Differential Sensitivity of Proliferating Lymphoid and Epithelial Cells to the Cytotoxic and Growth-Inhibitory Effects of Methotrexate

Abstract

Although methotrexate (MTX) is one of the most clinically effective therapies employed to treat psoriasis, the mechanism by which low-dose MTX acts to modulate the hyperplasia of psoriasis, leading to the restoration of clinically normal skin, is only partially understood. MTX has been considered a cytotoxic agent that mediates its effect primarily on proliferating or cycling epidermal cells. Recently, proliferating lymphoid cells have been identified in psoriatic lesions, raising the possibility that proliferating lymphoid cells could be another target cell that is killed by MTX. In this study, we examined the growth-inhibitory and cytotoxic effects of MTX on proliferating lymphoid cells [THP-1 (macrophage), and MOLT-4 (T cell)], epithelial cells (HeLa, and HaCat), and normal human keratinocytes (NHK) in vitro. The proliferating cells were exposed to MTX for 24 h, and placed in fresh media to mimic the transient MTX blood levels that result from once-weekly therapy. THP-1 and MOLT-4 were found to be 10-100 times more sensitive to the cytotoxic effects of MTX than were HeLa and HaCat, and more than 1000 times more sensitive than primary human keratinocytes. At MTX concentrations that would be expected to occur in vivo during once-weekly therapy, a large percentage (> 95%) of proliferating lymphoid targets would be killed, and only a small percentage (< 10%) of proliferating epidermal cells would be affected. This in vitro data suggests that in psoriasis proliferating lymphoid cells are more likely than epithelial cells to be a major cellular target of MTX in vivo.

Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.

“…Recent evidence implicates aberrant activation of the immune system and T lymphocyte localization in skin as critical components in the pathogenesis of psoriasis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), but the etiologic defect(s) in this disease remain elusive. A role for upregulated expression of autocrine regulatory networks in the pathogenesis of psoriasis has emerged from previous investigations that have suggested that epidermal hyperplasia and aberrant differentiation may result from dysregulation of the epidermal keratinocyte EGF receptor-ligand system (26, 31-35, 38, 39).…”

“…Although the etiology of psoriasis has not been elucidated, the development of psoriatic skin lesions has been shown to be associated with infiltration of cells from the immune system, including T lymphocytes, macrophages, and neutrophils. The aberrant activity of activated T lymphocytes is thought to be paramount in the pathogenesis of psoriasis, as immunosuppressive agents such as methotrexate, cyclosporine, tacrolimus, IL-2 receptor-targeted toxins, and corticosteroids are efficacious for this disease (1)(2)(3)(4)(5)(6). Furthermore, activated CD4-positive T lymphocytes from patients with psoriasis have been shown to initiate psoriatic lesion formation in uninvolved human psoriatic skin grafted onto SCID/SCID (severe combined immunodeficient) 1 (7,8), and SCID/SCID mice reconstituted with naive CD4-positive T lymphocytes possessing a minor histocompatibility mismatch have been reported recently to initiate a psoriatic-like cutaneous reaction (9).…”

Up-regulation of Id1 in peripheral blood of psoriatic patients

“…In histopathology, mixed inflammatory infiltrates are observed, primarily consisting of lymphocytes and monocytes (Ackerman, 1978). In recent years, it has been revealed that psoriatic skin lesions respond to certain immunosuppressive agents such as methotrexate, cyclosporine and macrolide immunosuppressants (Jeffes et al, 1995;Ozawa et al, 1999;Marsland and Griffiths, 2002). Another frequently used treatment modality in psoriasis, referred to as phototherapy, targets principally immune cells located in the epidermis and dermis (Vallat et al, 1994).…”

Change of TGF-β1 concentration in blood serum of patients during systemic treatment of severe psoriasis

“…Simultaneous use of narrow band 311 UVB phototherapy and metotrexate during the treatment of psoriasis is rare, as this synergy can increase risk of carcer. In addition, methotrexate has a photosensitive effect (Cueller et al, 1997;Jeffes et al, 1995).…”