Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA Ò to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells-2 (TREM-2) was among the mRNAs identified as being expressed by unactivated microglia, but down-regulated by lipopolysaccharide/interferon c. In the healthy CNS, not all microglia expressed TREM-2. Microglial expression of TREM-2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood-brain barrier had the lowest percentages of TREM-2-expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM-2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) Tissue-specific inflammation is dependent on more than simply the presence of an antigen within a tissue and an immune response mounted against that antigen. The onset, progression and termination of inflammatory responses are largely dependent on how the resident tissue macrophage/ dendritic cell interacts with both stromal tissue and tissueinfiltrating immune cells (Medzhitov and Janeway 1998;Lo et al. 1999). These interactions can shape antigen-independent and antigen-dependent immune responses toward the production of toxic molecules capable of destroying not only pathogens but also the tissues themselves. Such events have been argued to contribute to catastrophic neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and stroke (Kreutzberg 1996;Stoll and Jander 1999;Becher et al. 2000;Streit 2000;Aloisi 2001;Schwab et al. 2001;Campanella et al. 2002;Togo et al. 2002). Antigen presentation within the CNS by either microglia and/or CNS-infiltrating macrophages/dendritic cells may also mute and may potentially redirect antigen-specific immune responses toward the production of trophic factors (Ford et al. 1996;Raivich et al. 1998;Carson et al. 1999a;Kerschensteiner et al. 1999;Serpe et al. 1999). Such interactions have been suggested to contribute to the generation of immunological privilege and promotion of neuronal survival in the CNS (Schwartz et al. 1999;Streit 2000).The tissue macrophages of the brain are the microglia (Kreutzberg 1996;Streit 2000;Aloisi 2001). They are found in all brain regions, often in close apposition with neurons, and comprise between 5 and 15% of cells in the CNS. Abbreviations used: BBB, blood-brain barrier; Ct, cycle threshold; IRG, interferon response gene; IFN, interferon; LPS, lipolysaccharide; MHC, major histocompatibility complex; SSC, saline sodium citrate buffer; svTREM-2b, splice variant of triggerin...

Peyer's patch follicle-associated epithelium (FAE) regulates intestinal antigen access to the immune system in part through the action of microfold (M) cells which mediate transcytosis of antigens and microorganisms. Studies on M cells have been limited by the difficulties in isolating purified cells, so we applied TOGA mRNA expression profiling to identify genes associated with the in vitro induction of M cell-like features in Caco-2 cells and tested them against normal Peyer's patch tissue for their expression in FAE. Among the genes identified by this method, laminin beta3, a matrix metalloproteinase and a tetraspan family member, showed enriched expression in FAE of mouse Peyer's patches. Moreover, the C. perfringens enterotoxin receptor (CPE-R) appeared to be expressed more strongly by UEA-1(+) M cells relative to neighboring FAE. Expression of the tetraspan TM4SF3 gene and CPE-R was also confirmed in human Peyer's patch FAE. Our results suggest that while the Caco-2 differentiation model is associated with some functional features of M cells, the genes induced may instead reflect the acquisition of a more general FAE phenotype, sharing only select features with the M cell subset.

The Plainview/Folsom-aged bison Bonebed 2 at Bonfire Shelter, originally excavated in the 1960s, is argued to be the earliest North American bison jump (Dibble 1970; Dibble and Lorrain 1968). Yet, it is far older than all other known jumps, and well south of where the great majority of these sites are found. Dibble (1970) reasonably argued that its age and location was not compelling evidence against it being a bison jump. However, Binford (1978) observed that the skeletal composition of Bonebed 2 did not resemble a kill. To assess whether Bonfire Shelter could have been utilized as a jump and whether it was, we explore two lines of evidence bearing on the issue, a GIS analysis of the site and upland topography, and zooarchaeological analysis of the recovered bison remains. Although our GIS analysis indicates that Bonfire Shelter meets many of the criteria of a jump locality, our reanalysis of the faunal remains suggests this was not the primary kill locus, but instead a processing area to which high-utility portions of at least 24 bison were transported and butchered. Where the bison were killed, and how, is not known.

No abstract

Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) are upregulated in vascular endothelial and smooth muscle cells by cytokines produced at sites of inflammation. The cytokine profile for induction of VCAM-1, however, is different for the two cell types. Tumor necrosis factor-alpha (TNF-alpha) induced both VCAM-1 and ICAM-1 expression in human umbilical vein endothelial cells (HUVECs; ED50 approximately 300 and 30 U/ml, respectively). TNF-alpha and interleukin-1beta (IL-1beta) stimulated cell surface ICAM-1 expression, but not VCAM-1 expression, in human aortic smooth muscle cells (HASMCs). Conversely, IL-4 was a potent VCAM-1 inducer in HASMCs (ED50 approximately 100 pg/ml) but did not induce ICAM-1 expression. Nuclear extracts from IL-4-treated cells were compared with untreated cells for relative nuclear factor-kappa B (NF-kappaB) levels by using an electrophoretic mobility shift assay and surface plasmon resonance techniques. No significant increase in nuclear NF-kappaB DNA binding activity was detected in IL-4-treated HASMCs by either method of analysis. IL-1beta and TNF-alpha stimulated nuclear NF-kappaB levels by about fourfold and fivefold, respectively, in HASMCs. The antioxidant pyrrolidine dithiocarbamate (PDTC) similarly inhibited VCAM-1 upregulation in HASMCs incubated with IL-4 and in HUVECs incubated with TNF-alpha (IC50s of 25 and 40 microM, respectively). These data suggest that a significant increase in nuclear NF-kappaB levels is not necessary or sufficient for VCAM-1 upregulation in HASMCs and does not determine the relative sensitivity to inhibition of gene expression by PDTC.