In the present study, we examined the cytokine pattern expressed in situ during the development of eczematous reactions that had been provoked in atopic dermatitis patients by patch testing with house dust mite allergen. In 24-h house dust mite allergen patch test reactions, expression of interleukin (IL)-4 mRNA and IL-2 mRNA increased, but interferon (IFN)-gamma mRNA did not, as compared with control skin. In 48-h inhalant allergen patch test reactions, however, IFN-gamma mRNA and IL-2 mRNA expression were increased above levels observed in control skin, whereas IL-4 mRNA expression was decreased below background levels. These data demonstrate that a switch from a Th2-like to a Th1-like cytokine response occurs in inhalant allergen patch tests of atopic dermatitis patients. This biphasic pattern was specific to inhalant allergen patch test reactions, as it was not observed in irritant reactions in the same patient. IFN-gamma production by T cells may be induced by the cytokine IL-12. In the present study, up-regulation of IFN-gamma mRNA expression in inhalant allergen patch test reactions was preceded by an increased expression of the p35 subunit of IL-12 mRNA. These observations suggest that increased IL-12 expression may contribute to the observed switch of the in situ cytokine secretion pattern. Further studies are necessary to determine whether a similar biphasic pattern of cytokine expression is also operative in the initiation phase of atopic eczema.
Keratinocytes are the primary cellular target for ultraviolet radiation in human skin, and ultraviolet radiation-induced therapeutical effects may thus be mediated by keratinocyte-derived, antiinflammatory mediators. Interleukin-10 is capable of exerting antiinflammatory effects by virtue of its capacity to suppress the production of interferon-gamma. The present study therefore assessed the ability of cultured human keratinocytes to produce interleukin-10 following ultraviolet irradiation. Exposure of long-term cultured normal human keratinocytes to ultraviolet B (280-320 nm) or to ultraviolet A1 (340-400 nm) radiation caused a time- and dose-dependent induction of interleukin-10 mRNA expression and interleukin-10 protein secretion, with ultraviolet A1 radiation being the strongest stimulus. Ultraviolet radiation-induced interleukin-10 production by normal human keratinocytes was enhanced by a factor of two, when cells were cultured in high- rather than low-calcium medium. Neither addition of the ultraviolet radiation-inducible cytokines tumor necrosis factor-alpha or interleukin-1 alpha to unirradiated keratinocytes nor presence of their respective neutralizing antibodies in cultures of irradiated keratinocytes induced or inhibited interleukin-10 synthesis. Modulation of eicosanoid production by addition of prostaglandin E2 to keratinocyte cultures or disturbance of cyclooxygenase activity by indomethacin did not affect interleukin-10 production in resting or irradiated cells. These studies demonstrate that cultured human keratinocytes are capable of producing interleukin-10. Human keratinocyte interleukin-10 production is dependent on the differentiation state of the cell and induced by ultraviolet B and, in particular, ultraviolet A1 radiation exposure. This novel property of ultraviolet radiation may account at least in part for the efficacy of phototherapy in inflammatory skin diseases.
The cytokine interleukin (IL)‐6 has recently been demonstrated to play a role in the pathology of Alzheimer's disease (AD). The mechanisms leading to increased IL‐6 levels in brains of AD patients are still unknown. Because in experimental animals ischemia increases both the level of cytokines and the extracellular concentrations of adenosine in the brain, we hypothesized that these two phenomena may be functionally connected and that adenosine might increase IL‐6 gene expression in the brain. Here we show that the mixed A1 and A2 agonist 5′‐(N‐ethylcarboxamido)adenosine (NECA) induces an increase in IL‐6 mRNA levels and protein synthesis in the human astrocytoma cell line U373 MG. The A1‐specific agonists R‐phenylisopropyladenosine and cyclopentyladenosine are much less potent, and the A2a‐specific agonist CGS‐21680 shows only marginal effects. Increased levels of mRNA are already found within 30 min after NECA treatment. The A2a‐selective antagonists 8‐(3‐chlorostyryl)caffeine and KF17837 [(E)‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐7‐methylxanthine], which have also some antagonistic properties at A2b receptors, and the nonspecific adenosine antagonist 8‐phenyltheophylline were equipotent at inhibiting the NECA‐induced increase in IL‐6 protein synthesis, whereas the specific A1 antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine is much less potent. The results indicate that adenosine A2b receptors participate in the regulation of the IL‐6 gene in astrocytoma cells.
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