Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis.

Abstract

In addition to being T lymphocyte-driven, psoriasis may be due in part to abnormal integrin expression. Normal-appearing (uninvolved) skin from psoriatic patients was examined to determine whether altered fibronectin or its receptor expression is detectable before development of psoriatic lesions. In contrast to skin from normal subjects, we detect by immunofluorescence the abnormal presence of plasma fibronectin in the basal cell layer of the epidermis of psoriatic uninvolved skin. Furthermore, increased fibronectin exposure superinduces the in vitro cell cycle induction and expansion of psoriatic nonlesional keratinocytes in response to a cocktail of T cell lymphokines. Fibronectin alone also appeared to increase cell cycle entry among uninvolved but not normal keratinocytes. Concordantly, the alpha5 integrin fibronectin receptor, but not alpha2 or alpha3, is overexpressed in the in vivo nonlesional psoriatic epidermis. The involvement of alpha5beta1 in the early outgrowth of clonogenic keratinocytes in the ex vivo culture was demonstrated by the ability of anti-alpha5 mAb to inhibit keratinocyte growth on fibronectin. Thus, the fibronectin receptor appears to be one of the components required for the development of the hyperresponsiveness of psoriatic keratinocytes to signals for proliferation provided by lymphokines produced by intralesional T lymphocytes in psoriasis.

Identification and Characterization of a Novel, Psoriasis Susceptibility-related Noncoding RNA gene, PRINS

“…Some of the identified transcripts encode proteins with already characterized functions, such as the extracellular matrix protein, fibronectin. The high expression of fibronectin in psoriatic uninvolved epidermis is in good agreement with previous findings demonstrating the expression of fibronectin at the dermal-epidermal junction of psoriatic uninvolved but not of normal epidermis (15,21). Another transcript showing elevated expression in psoriatic uninvolved epidermis was RAB10, a member of the ras oncogene family.…”

“…Keratinocytes in the uninvolved skin of psoriatic patients have an inherent sensitivity to proliferative signals, and this elevated sensitivity plays a crucial role in the development of psoriatic lesions (14,15). Hence, identification of differentially expressed genes in the uninvolved epidermis of psoriatic patients compared with healthy epidermis may reveal novel psoriasis susceptibility factors.…”

Integrins in Wound Healing

“…24 The interaction of a 5 b 1 integrin with fibronectin may also contribute to keratinocyte proliferation in addition to promoting their adhesion and motility on this matrix. 117 Epithelial a v b 6 integrin regulates inflammation and granulation tissue remodeling. When the migrating epithelial fronts originating from the wound edges have joined and cover the wound surface, b 1 integrin expression is downregulated, and a 6 b 4 integrin binding to laminin-332 is restored.…”

Abnormális STAT1 aktivitás pikkelysömörben

“…Pikkelysömörös fibroblasztokban ezzel ellentétben nem figyelhetô meg az aktivált STAT1 FN1 és EDA + FN kifejezôdést gátló funkciója (18). Eredmé-nyeink alapján feltételezhetô, hogy a pikkelysömörös bôr-ben leírt fokozott FN és EDA + FN kifejezôdés (6,23) hát-terében részben a STAT1 abnormális funkciója állhat. Az aktivált STAT1 kifejezôdése a normál bôrben arra utal, hogy a szövet homeosztatikus állapotának fenntartásában a STAT1 aktiváció szerepet játszik.…”

“…Emellett fokozottan infiltrálódó T-limfociták, neutrofilek és leukociták, emelkedett növekedési faktor, citokin és kemokin kifejezôdés figyelhetô meg pikkelysömörös tü-netes bôrben a celluláris immunrendszer aberráns aktivá-ciójának köszönhetôen (2)(3)(4). A makroszkópikusan normális fenotípust mutató, tünetmentes pikkelysömörös bôr -saját és más kutatócsoportok eredményei szerintkülönbözô eltéréseket hordoz magában az egészségeshez képest (5,6).…”