In Vitro and In Vivo Expression of Interleukin-1α and Tumor Necrosis Factor-α mRNA in Pemphigus Vulgaris: Interleukin-1α and Tumor Necrosis Factor-α are Involved in Acantholysis

Abstract

Keratinocyte-derived cytokines have been implicated in the pathogenesis of a number of skin diseases. In this study we examined the possible role of keratinocyte-derived cytokines in the development of acantholysis in pemphigus vulgaris. Nineteen patients with pemphigus vulgaris, demonstrating the characteristic clinical, pathologic, and immunopathologic findings were studied. In situ immunolabeling demonstrated the presence of two cytokines interleukin-1alpha and tumor necrosis factor-alpha, in lesional and perilesional areas. Results were confirmed by reverse transcriptase-polymerase chain reaction, demonstrating overexpression of both cytokines in vivo. To study the role of these cytokines in the pathogenesis of pemphigus vulgaris both in vitro and in vivo studies were performed. The results of the in vitro study demonstrated that pemphigus vulgaris IgG induced interleukin-1alpha and tumor necrosis factor-alpha mRNA in the skin. The potential pathogenic role of these mediators was demonstrated by a blocking study using antibodies against human interleukin-1alpha and tumor necrosis factor-alpha in keratinocytes cultures. A combination of anti-interleukin-1alpha and anti-tumor necrosis factor-alpha antibodies inhibited in vitro pemphigus vulgaris IgG induced acantholysis. To confirm the role of interleukin-1 and tumor necrosis factor-alpha in pemphigus, we utilized passive transfer studies using interleukin-1 deficient mice (ICE-/-, interleukin-1beta-/-) and tumor necrosis factor-alpha receptor deficient mice (TNFR1R2-/-). Both groups demonstrated a decreased susceptibility to the passive transfer of pemphigus. Our data support the role of cytokines interleukin-1 and tumor necrosis factor-alpha in the pathogenesis of pemphigus vulgaris.

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

“…The group of affected genes included those encoding cytokines and cytokineinducible proteins, which is in keeping with observations that pemphigus antibodies can modulate the cytokine production in KC (93,94). Finally, changes of apoptosis-related genes may underlie the appearance of an apoptotic phenotype in KC prior to cell-cell detachment (acantholysis) in the skin of pemphigus patients (95).…”

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

“…71 TNF-␣ has been shown to activate calpains because of a rise in the concentration of intracellular free Ca 2ϩ . 72 It is well established that TNF-␣ is elevated in the serum of PV patients, [73][74][75][76] deposited in the lesional skin, 77,78 present in the blister fluid, 74 and up-regulated in keratinocytes due to PV antibody binding 78,79 and that anti-TNF-␣ therapy with etanercept (a fusion protein of TNF-␣ receptor) can ameliorate recalcitrant PV. 80,81 During cell injury, calpain functions as a signal to mediate the influx of extracellular Ca 2ϩ after ATP depletion and endoplasmic reticulum Ca 2ϩ release.…”

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

“…In AIBD, increased cytokine expression in several compartments, including serum, blister fluid, and skin, has been well documented (6). However, with the exception of two studies, one indicating the involvement of IL-1 and TNF-a in the pathogenesis of pemphigus vulgaris (7) and the other indicating an anti-inflammatory role for IL-6 in epidermolyis bullosa acquisita (EBA) (8), no functional data are available. Expression profiling identified IL-1ra as 1 of 33 gene products expressed differentially in the skin of BALB/c mice with experimental EBA.…”