The cytokine interleukin-1 (IL-1) is a major inflammatory hormone which activates a broad range of genes during inflammation. The signaling mechanisms triggered by IL-1 include activation of several distinct protein kinase systems. The stress-activated protein kinase (SAPK), also termed Jun N-terminal kinase (JNK), is activated particularly strongly by the cytokine. In an attempt to delineate its role in activation of gene expression by IL-1, we inhibited the IL-1-induced SAPK/JNK activity by stable overexpression of either a catalytically inactive mutant of SAPK␤ (SAPK␤(K-R)) or antisense RNA to SAPK␤ in human epidermal carcinoma cells. A detailed analysis of signal transduction in those cells showed that activation of neither NFB nor p38 mitogen-activated protein kinase was affected, suggesting that we achieved specific blockade of the SAPK/JNK. In untransfected and vector-transfected KB cells, IL-1 induced a strong increase in expression of IL-6 and IL-8 mRNA, along with the synthesis of high amounts of the proteins. In two KB cell clones stably overexpressing the mutant SAPK␤(K-R), and three clones stably overexpressing antisense RNA to SAPK␤, expression of IL-6 and IL-8 in response to IL-1 was strongly reduced at both the mRNA and protein level. These data indicate that the SAPK/JNK pathway provides an indispensable signal for IL-1-induced expression of IL-6 and IL-8.

Time-distinct gene induction of IL-1beta, TNFalpha and IL-1beta is involved in UV-induced immune reactions, but no considerable changes were found for IL-10r or IL-7.

The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation.

There is growing public concern about the possible health risks, particularly increased cancer risks of exposure to magnetic fields (MF) associated with power distribution systems. Recently, we have started a series of animal studies to investigate this issue, using the DMBA (7,12-dimethylbenz[a]anthracene) model of breast cancer in female rats. In the present study, female rats were chronically exposed to a 50-Hz, 50 jlTesla (uT) MF with or without DMBA treatment Because alterations in circulating levels of the pineal hormone melatonin and impaired immune system functions have been involved in breast cancer growth, and both melatonin and immune system are thought to be targets for MF-effects, serum melatonin and the proUferative capacity of splenic lymphocytes were determined in MF-exposed and sham-exposed rats. For this purpose, 216 female Sprague-Dawley rats were divided into four groups. Two of the groups (with 99 animals each) received oral applications of DMBA and were either shamexposed or exposed in a 50-Hz, 50 uT MF for 24 h/day 7 days/week for a period of 91 days. The other two groups (9 animals each) were either sham-exposed or MF-exposed without DMBA treatment. The exposure chambers and all other environmental factors were identical for MF-exposed and sham-exposed animals. The DMBA-treated animals were palpated once weekly to assess the development of mammary tumors. At the end of the three-month period of MF exposure, the number and size of mammary tumors was determined by autopsy. In controls, DMBA induced tumors in -55% of the animals within the 3 month period of sham-exposure. Already 8 weeks after DMBA application, the MF-exposed group exhibited significantly more tumors than sham-exposed animals. At time of autopsy, significantly more MF-exposed DMBA-treated rats exhibited macroscopically visible mammary tumors than DMBAtreated controls, thus indicating that MF exposure enhances the development and growth of cancers in this model. Comparison of the data from 50 |iT with recent data from other flux densities indicated that long-term MF exposure of DMBA-treated rats increases the incidence of palpable and/or macroscopically visible mammary tumors in a highly dose-related fashion. Determination of nocturnal serum melatonin after 9 and 12 weeks of exposure at 50 \iT did not yield significant differences between MF-exposed rats and sham-exposed controls, whereas a marked suppression of T cell proliferative capacity was seen in MF exposed•Abbreviations: CON A, concanavalin A; DMBA, 7,l2-dimethylbenz[a]-anthracene; MF, magnetic field; ODC, omithine decarboxylase; T, Tesla.© Oxford University Press rats. The data add further evidence to the hypothesis that hormone-dependent tissues such as breast might be particularly sensitive to MF-effects and indicate that immune system depression is involved in the increased breast cancer growth observed in MF exposed rats.

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