Bacterial lipopolypolysaccharide (LPS)-induced fever involves induction of the proinflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6, both in the periphery and in the brain. These molecules can induce expression of each other and also regulate expression of their own receptors in a complex manner. The functional hierarchy of these highly inducible proteins is therefore difficult to determine. Using mice strains carrying the null mutations of IL-1 beta, IL-1RI, IL-1RAcP, or IL-6, respectively, we show that LPS-induced fever involves IL-1 beta, which acts at a complex consisting of the type I IL-1 receptor and the IL-1RAcP. This action occurs prior to central IL-6 release, which has been shown to be a necessary component of fever responses induced by LPS, IL-1 beta, and also TNF-alpha. In the absence of IL-1 beta, as in IL-1 beta-deficient mice, LPS, IL-1 alpha, and IL-1 beta cause hyperresponsive fevers when exogenously applied. Murine TNF-alpha is a poor pyrogen in mice even when mice are kept at thermoneutral temperature (30 degrees C). TNF-alpha-mediated fever depends on central IL-6 expression.
One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques. The main constituent of the amyloid plaques is the amyloid beta-peptide (A beta) shown to activate glial cells in vitro. A growing body of evidence suggests that these cells contribute to neurotoxicity through production of inflammatory cytokines, chemokines, and neurotoxic substances, such as reactive oxygen species (ROS). In this study, mRNA levels of the inflammatory cytokines interleukin (IL)-1alpha and beta, and IL-6 were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) in rat primary mixed glial cells after treatment with A beta(25-35), a biologically active fragment of A beta peptide with neurotoxic properties. Clear morphological changes of the astrocytes, as well as proliferation and clustering of microglial cells were observed by light and immunofluorescence microscopy after 24 h treatment. Significant increases in IL-1alpha and IL-6 mRNA levels were detected after 24 and 72 h, whereas significantly increased levels of IL-1beta mRNA could only be detected after 4 h treatment. The most pronounced effect was seen on IL-6 mRNA expression, which increased approx two- to threefold after treatment. In addition, increased secretion of IL-6 was detected after 96 h exposure. Recently, association of IL-1alpha and IL-6 gene polymorphism with AD was reported, suggesting that these cytokines may play an important role in the development of the disease. The increased mRNA levels of IL-1alpha and IL-6 in parallel with the morphological changes in the mixed glial-cell cultures support that these cytokines may be involved in A beta-induced gliosis and in the pathogenesis of AD.
IL-1alpha and IL-1beta are potent inflammatory cytokines that contribute to a number of normal physiologic processes and to the development of a number of inflammatory diseases. Two IL-1R, the type I and type II receptors, have been identified. This work describes the derivation and characterization of mice deficient in expression of the type I IL-1R (IL-1RI). IL-1RI-deficient mice were viable and fertile, but failed to respond to IL-1 in a variety of assays, including IL-1-induced IL-6 and E-selectin expression and IL-1-induced fever. Similar to IL-1beta-deficient mice, IL-1RI-deficient mice had a reduced acute phase response to turpentine. In contrast, IL-1RI-deficient mice had a reduced delayed-type hypersensitivity response and were highly susceptible to infection by Listeria monocytogenes. These data demonstrate that the IL-1RI is essential for all IL-1-mediated signaling events examined, and that both IL-1alpha and IL-1beta are critical to the animals' response to injury and infection. These data also demonstrate that IL-1 function is not required for normal development or homeostasis.
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