Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

Objective. To examine the effects of intraarticular induction of interleukin-1␤ (IL-1␤) expression in adult mice.Methods. We used somatic mosaic analysis in a novel transgenic mouse with an inducible IL-1␤ transcription unit. Transgene activation was induced by Cre recombinase in the temporomandibular joints (TMJs) of adult transgenic mice (conditional knockin model). The effects of intraarticular IL-1␤ induction were subsequently evaluated at the cellular, histopathologic, and behavioral levels. Osteoarthritis (OA) manifests as a slowly progressing debilitating disease that affects one or more joints of the body. Clinical symptoms include pain, dysfunction, and swelling and enlargement of the joints. The primary pathologic features of OA are fibrillation and loss of articular cartilage, accompanied by remodeling of subchondral bone. OA seems to be a node of convergence for a number of potentially independent pathologic processes that, ultimately, can lead to joint dysfunction and pain (1). Although the role of inflammation in OA has been long debated (2), recent evidence now confirms proinflammatory cytokines as mediators in this disease (3). For example, the catabolism of OA cartilage is thought to involve the action of proinflammatory cytokines such as interleukin-1 (IL-1)

The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E 2 (PGE 2 ) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE 2 synthesis was enhanced. Inhibition of PGE 2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin downregulation. In contrast, addition of PGE 2 or the EP2 receptor agonist butaprost to PMK produced a dose-and timedependent decrease in E-cadherin. We also show that UV irradiation, via the PGE 2 -EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating Ecadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE 2 -EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654-64]

BackgroundThe purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo.MethodsWe employed the inducible Col1-IL1βXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology.ResultsInduction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1βXAT compound transgenic mouse.ConclusionThis work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.