Smad7 positively regulates keratinocyte proliferation in psoriasis

Abstract

Background

Transforming growth factor (TGF)-β1 exerts inhibitory effects on keratinocyte proliferation.

Objectives

To examine whether Smad7, a known inhibitor of TGF-β1 signalling, is involved in the psoriasis-associated keratinocyte hyper-proliferation.

Methods

Smad7 was evaluated in skin sections of psoriatic patients and healthy controls and in mice with Aldara-induced skin pathology by real-time PCR and immunohistochemistry. To assess whether Smad7 positively regulates the in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K) 6 and K16, cell cycle-associated factors, cell cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS.

Results

Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in S-phase of cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through S phase, and hyper-phosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness.

Conclusions

Our data show that Smad7 is over-expressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.

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