Psoriatic keratinocytes show reduced IRF‐1 and STAT‐1α activation in response to γ‐IFN

Abstract

Psoriasis is a chronic inflammatory dermatosis characterized by hyperproliferative keratinocytes (KC). The skin lesions are infiltrated by T cells, which secrete gamma interferon (gamma-IFN) and are believed to be necessary to maintain the psoriatic phenotype. In normal KC, gamma-IFN is a potent inhibitor of proliferation, but proliferation of KC persists in psoriatic plaques despite the presence of gamma-IFN. Immunostaining of interferon regulatory factor-1 (IRF-1) revealed that IRF-1 was localized to the basal cells of the epidermis in normal and in nonlesional psoriatic skin, but was suprabasal or completely absent in lesional psoriatic skin. This finding led to the hypothesis that abnormal signaling in the gamma-IFN pathway may occur in psoriatic KC. To test this hypothesis, we measured activation of IRF-1 and signal transducer and activator of transcription (STAT)-1alpha transcription factors in KC after stimulation with gamma-IFN. Primary cultures of KC from normal and nonlesional psoriatic skin were stimulated with gamma-IFN and subsequent transcription factor activation was measured by electrophoretic mobility shift assay. Psoriatic KC showed a reduced induction of IRF-1 and STAT-1alpha activation after stimulation with gamma-IFN, compared with normal KC. Reduced activation of IRF-1 and STAT-1alpha in response to gamma-IFN indicates a fundamental defect in the growth and differentiation control of psoriatic KC in the absence of the influence of other cell types.

CD56brightCD16– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

“…Cross-talk between IFN-c-releasing lymphocytes and keratinocytes is critical for psoriasis development and persistence. Although IFN-c has antiproliferative activity on normal keratinocytes, it failed to block cell cycling in psoriatic keratinocytes and decreased STAT-1 and IRF-1, which are both involved in the regulation of keratinocyte responsiveness to IFN-c [4,5].…”

“…Epidermal changes, consisting of keratinocyte hyperproliferation and altered differentiation, are believed to depend on genetically determined dysregulation of gene expression pathways involved in keratinocyte responsiveness to leukocyte-derived proinflammatory signals [4][5][6]. The role of the immune system in the pathogenesis of the disease has been widely documented [7,8].…”

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

“…This notion is based on the presence of T lymphocytes in early psoriasis lesions (16), the beneficial effects of T lymphocyte-targeted therapies such as cyclosporin A (8), and the altered relationship between psoriatic keratinocytes and interferon-␥ (IFN␥) compared with normal keratinocytes (17). Data on the role of T cells in PsA are limited, but it has been suggested that they play a central role in its pathogenesis as well (18)(19)(20).…”

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology

“…Intensive family studies since the early 1950s and linkage analysis studies pointed out several genetic loci that play a role in psoriasis (Bhalerao et al, 1998). In the last decade, a molecular biology approach emerged to identify abnormally expressed genes and proteins contributing to psoriasis (Jackson et al, 1999) (Chen et al, 2000). Two major genes under investigation are IL12B on chromosome 5q, which expresses interleukin-12B; and IL23R on chromosome 1p, which expresses the interleukin-23 receptor, and is involved in T cell differentiation.…”