Pentoxifylline Inhibits T-Cell Adherence to Keratinocytes

Abstract

In many inflammatory dermatoses leukocyte function-associated antigen-1/intercellular adhesion molecule-1 mediated T-cell/keratinocyte adhesion is considered to play an important role. Pentoxifylline (PTX), a methylxanthine derivative widely used for the symptomatic treatment of various vascular disorders, was recently found to have anti-inflammatory effects. PTX can suppress tumor necrosis factor-alpha production and function, and inhibits leukocyte-endothelial cell adherence. The aim of the present study was to investigate whether PTX also interferes with T-cell/keratinocyte binding. Peripheral blood T cells were activated with phorbol myristate acetate and co-incubated with interferon-gamma- or tumor necrosis factor-alpha-stimulated keratinocytes (SVK 14 cells) in the presence or absence of PTX. Using an enzyme-linked immuno cell adhesion assay PTX was found to inhibit T-cell/keratinocyte adhesion in a dose-dependent manner. A similar inhibition was found when PTX was replaced by isobutylmethylxanthine, another methylxanthine derivative, or by a combination of two cyclic adenosine monophosphate analogues. No major effect on T-cell/keratinocyte adherence was observed when PTX was present during the pre-incubation of keratinocyte monolayers with tumor necrosis factor-alpha or interferon-gamma prior to the adhesion assay. In keratinocyte monolayers the interferon-gamma or tumor necrosis factor-alpha induced intercellular adhesion molecule-1 expression could not be inhibited by PTX. However, when PTX was added to short-term organ cultures of normal human skin biopsies, the lipopolysaccharide- and tumor necrosis factor-alpha-induced keratinocyte intercellular adhesion molecule-1 expression was blocked completely. The interferon-gamma-induced ICAM-1 expression was not blocked by PTX. The results presented herein suggest that impaired T-cell/keratinocyte binding may be one of the mechanisms by which PTX exerts a beneficial effect in certain inflammatory dermatoses.

Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components

“…Kovach et al has shown that PTX can inhibit integrin mediated adherence of IL-2 activated PBLs to HUVECs, matrix components and cultured tumor cells. 32 Studies by other groups have shown that PTX can inhibit the adhesion of T cells to keratinocytes 33 and endothelioma cells. 34 Our study shows that the inhibition in adhesion of F10 cells to ECM components was evident only up to four hours and further incubation with the drug for 24 hours in fact brought about a significant increase in adhesion.…”

Lymphocyte-Fibroblast Interactions

“…On the basis of circumstantial evidence, it has been revealed that thymic cortical epithelial cells form a web or network that makes close contact with immature (CD4 and CD8 double-positive) T-lymphocytes undergoing positive selection. Interaction of T-lymphocytes with epidermal keratinocytes has also been reported (Singer et al, 1990;Stoof et al, 1992;de Haan et al, 1994;Bruynzeel et al, 1995). It was speculated that such interactions may play a critical role for the extrathymic or post-thymic events in T-lymphocyte maturation (Parker et al, 1990).…”

Pentoxifylline in the Treatment of Actinic Prurigo

“…PTX also downregulates the expression of adhesion molecules in human keratinocytes, T lymphocytes and epidermal Langerhans cells [15, 17, 18, 28]. Hydroxyl radical scavenger properties have also been described for PTX [22].…”

“…Besides its hemorheologic activity, PTX has been found to suppress the production of TNF-α by murine and human leukocytes [14, 15, 16]. Moreover, recent reports have described that PTX inhibits T-cell adherence to keratinocytes and the activation of human T lymphocytes [17, 18]. Therefore, considering these anti-inflammatory effects, we assessed the clinical efficacy of PTX for the treatment of AP patients while measuring its effects on erythema, papules and nodules as well as on the improvement of pruritus.…”