IL-27 Regulates IL-18 Binding Protein in Skin Resident Cells

IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48–72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts

Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

Role of Cortisol and Dehydroepiandrosterone on RACK1/PKC Signalling and Consequences in Immunosenescence

Over the past 15 years, it was demonstrated that defective protein kinase C (PKC) signal transduction machinery correlates to the decline of immune functions associated with aging. Experimental evidence suggest that altered PKC signalling results in impaired response to lipopolisaccaride (LPS) stimulation and cytokine release. Such defective signalling is due to reduced expression of receptor for activated C kinase 1 (RACK1) and to age-related alteration of the hormonal balance between cortisol and dehydroepiandrosterone (DHEA): cortisol levels remain substantially unchanged while DHEA levels decline with aging. These aspects are particularly relevant for the functional PKC signalling system because DHEA administration in vivo and in vitro in aged animals and in human cells can reestablish the levels of RACK1 and thus the function of the PKC signalling cascade. There is also evidence that cortisol and DHEA have opposite effect on the transcriptional regulation of the gene encoding for RACK1 and known as GNB2L1. At transcriptional level, cortisol has a peculiar function of a negative regulator of the RACK1 promoter, while the effect of DHEA seems to derive from a complex influence on the functions and post-transcriptional regulation of the glucocorticoid receptor (GR). Here we discuss the role of PKC/RACK1 signalling in the context of immune cells and immunosenescence also focusing on the role of cortisol and DHEA in the regulation of RACK1 expression