Urokinase plasminogen activator mRNA is induced by IL-1α and TNF-α in in vitro acantholysis

The role of urokinase type plasminogen activator (uPA) has been well documented in the pathogenesis of pemphigus vulgaris (PV). Activation of plasminogen into active serine protease plasmin initiates extracellular proteolysis leading to acantholysis but the mechanisms underlying this process are not clearly understood. We have previously shown that keratinocyte derived cytokines IL-1α and TNF-α are involved in PV-induced acantholysis. In the present study we sought to examine whether keratinocyte-derived IL-1α and TNF-α are correlated with uPA induction in keratinocytes during acantholysis. Normal human keratinocytes were incubated with diluted PV serum. mRNAs for IL-1α, TNF-α and uPA were examined with RT-PCR at various time points and acantholysis was measured. IL-1α, TNF-α and uPA mRNAs were all induced in keratinocytes following PV serum stimulation; IL-1α/TNF-α mRNAs' expression was earlier than the expression of uPA mRNA. To further examine the role of IL-1α, TNF-α and uPA in acantholysis, we performed antibody blocking studies. Anti-IL-la, anti-TNF-a and anti-uPA antibodies suppressed acantholysis by 76%, 80% and 90%, respectively. In addition, anti-IL-1α and anti-TNF-α antibodies inhibited uPA mRNA induction, whereas anti-uPA antibodies did not alter IL-1α/TNF-α mRNAs' expression. Our results confirm the role of uPA in acantholysis and suggest an involvement of IL-1α/TNF-α in uPA induction. © Blackwell Munksgaard, 2003

TNFα and its receptors in psoriatic skin, before and after treatment with etanercept

Psoriasis is a chronic inflammatory skin condition characterized by inflammatory dermal infiltrate and hyperproliferative keratinocytes. The pathogenesis of this disease is mediated by a dysregulation of the innate immunity and cytokine production. Tumor Necrosis Factor alpha (TNFα) is considered the most important cytokine involved in the pathological mechanism of psoriasis. Recently, several therapies have been introduced for the treatment of psoriasis that try to block TNF alpha activity. Among these treatments Etanercept is a fusion protein that specifically targets TNF alpha. We performed a study on twelve psoriatic patients aimed at evaluating the effect of Etanercept treatment on the production and expression of TNFα and its receptors, in lesional and uninvolved psoriatic skin. We demonstrated that after three month of Etanercept treatment at 50 mg/wk, TNF, TNF-RI and TNF-RII immunostaining in lesional and non-lesional skin samples of patients was greatly reduced, suggesting that this treatment not only acts on stable lesional plaques, but also at a very early stage of the disease. Copyright © by Biolife, s.a.s

Interferon β-1b modulates MCP-1 expression and production in relapsing-remitting multiple sclerosis

Monocyte chemoattractant protein-1 (MCP-1) seems to be involved in the pathogenesis of multiple sclerosis (MS). We found that in unstimulated (PHA-) and PHA-stimulated (PHA+) peripheral blood mononuclear cells (PBMC), MCP-1 and TNFα levels are higher in stable untreated MS patients. Interferon gamma (IFNγ) is higher in relapsing patients in PHA- cultures and in stable patients in PHA+ cultures. Chronic IFNβ-1b treatment down-regulates TNFα, IFNγ and MCP-1 production except for TNFα in relapsing patients. IFNβ-1b, in vitro, increases MCP-1, TNFα and IFNγ spontaneous production in all patients. Multivariate analysis suggests that MCP-1 production is dependent from clinical status and not from TNFα and IFNγ production. Logistic regression analysis shows that MCP-1 production is significantly modified by treatment. Further studies are needed to clarify the role of MCP-1 in MS. © 2002 Elsevier Science B.V. All rights reserved