Diagnostic dilemma of kimura disease of eyelids.

Kimura disease (KD) is a rare benign chronic inflammatory disease that presents as a nodule mostly involving deep subcutaneous tissue of the head and neck region with frequent regional lymphadenopathy and peripheral blood eosinophilia. KD shares some clinical and histopathological similarity with angiolymphoid hyperplasia with eosinophilia (ALHE). Consequently, KD and ALHE were once considered variants of the same disease spectrum. We present here rare cases of Kimura disease and ALHE involving the eyelid and lacrimal gland and discuss their differential features.

Monochloramine enhances Fas (APO-1/CD95)-induced apoptosis in Jurkat T cells.

Monochloramine derivatives are physiological oxidants produced by activated neutrophils. We report the effects of chemically prepared monochloramine (NH2Cl) on Fas-induced apoptosis in Jurkat T cells. When the cells were pretreated with NH2Cl (20-70 microM), subsequent addition of apoptosis-inducing anti-Fas antibody resulted in a synergistic enhancement of apoptosis. Treatment of NH2Cl (50-70 microM) alone resulted in a slight but definite apoptosis. Caspase activities, as measured by DEVD and IETD cleavage activities, were also elevated synergistically by NH2Cl + anti-Fas antibody stimulation. Moreover, a broad caspase inhibitor, Z-VAD-fmk, almost completely inhibited the apoptosis induced by NH2Cl and/or anti-Fas antibody. Fas expression on the Jurkat cell surface was not affected by the NH2Cl treatment. After 3 h of NH2Cl treatment, when the apoptosis was beginning to increase, the cells showed cytochrome c release from mitochondria, proteolytic activation of caspase 9, and poly (ADP-ribose) polymerase cleavage, regardless of Fas stimulation. Z-VAD-fmk almost completely inhibited this poly (ADP-ribose) polymerase cleavage, but not cytochrome c release. By contrast, Fas stimulation alone resulted in neither cytochrome c release nor caspase 9 activation at 3 h, and the increase in the DEVD cleavage activity and apoptosis became evident at later time points. These results suggested that NH2Cl enhanced Fas-induced apoptosis through the cytochrome c release and caspase 9 activation at the early stage of apoptosis. Chloramines derived from acute inflammation may modify immune reactions, such as cell-mediated cytotoxicity and some autoimmune diseases, by the enhancement of Fas-induced apoptosis.

Monochloramine inhibits etoposide-induced apoptosis with an increase in DNA aberration.

Monochloramine (NH(2)Cl) is a physiological oxidant produced by activated neutrophils, and it affects apoptosis signaling. We studied the effects of NH(2)Cl on the cell death induced by etoposide, a widely used anticancer agent that is directed to DNA topoisomerase II. Jurkat T cells, a human acute T cell leukemia cell line, were pretreated with 70 microM of NH(2)Cl for 10 min. After 24 h, 5-30 microM of etoposide was added to the NH(2)Cl pretreated and control cells, and their apoptosis, caspase activity, cell morphology, and cellular DNA contents were measured. NH(2)Cl pretreatment significantly inhibited apoptosis and caspase activation induced by etoposide or camptothecin, a DNA topoisomerase I poison, but not by staurosporine or Fas stimulation. The apoptosis inhibition actually resulted in the proliferation of the survived cells and, notably, the survived cells showed more aberrant morphology, such as variation in nuclear size, nuclear fragments, and multinucleated cells. DNA content analysis of the survived cells showed an increase in aneuploid nuclei. Cell cycle analysis after 24 h of NH(2)Cl treatment showed a significant decrease in S phase cells with a concurrent increase in G(0)/G(1) phase cells, which suggested that NH(2)Cl induced G(1) arrest. Using synchronized Jurkat cells, etoposide and camptothecin were found to be particularly cytotoxic to S phase cells, whereas staurosporine and Fas stimulation were not. Thus NH(2)Cl-induced G(1) arrest was a likely cause of the observed resistance to etoposide. These observations suggested that inflammation-derived oxidants may make the tumor cells more resistant to etoposide and increase the risk of tumor progression and the development of secondary tumors by increasing the survival of DNA damage-bearing cells.

JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death.

Our aim was to better understand the mechanism and importance of sustained c-Jun N-terminal kinase (JNK) activation in endoplasmic reticulum (ER) stress and effects of ER stress on mitochondria by determining the role of mitochondrial JNK binding protein, Sab. Tunicamycin or brefeldin A induced a rapid and marked decline in basal mitochondrial respiration and reserve-capacity followed by delayed mitochondrial-mediated apoptosis. Knockdown of mitochondrial Sab prevented ER stress-induced sustained JNK activation, impaired respiration, and apoptosis, but did not alter the magnitude or time course of activation of ER stress pathways. P-JNK plus adenosine 5'-triphosphate (ATP) added to isolated liver mitochondria promoted superoxide production, which was amplified by addition of calcium and inhibited by a blocking peptide corresponding to the JNK binding site on Sab (KIM1). This peptide also blocked tunicamycin-induced inhibition of cellular respiration. In conclusion, ER stress triggers an interaction of JNK with mitochondrial Sab, which leads to impaired respiration and increased mitochondrial reactive oxygen species, sustaining JNK activation culminating in apoptosis.