IL-23 is a recently discovered heterodimeric cytokine that shares biological properties with proinflammatory cytokines. The biologically active heterodimer consists of p19 and the p40 subunit of ...IL-12. IL-23 has been shown to possess biological activities on T cells that are similar as well distinct from those of IL-12. We have constructed single-chain IL-23 and IL-12 fusion proteins (IL-23-Ig and IL-12-Ig) and have compared the two recombinant proteins for effects on murine dendritic cells (DC). Here we show that the IL-23-Ig can bind a significant proportion of splenic DC of both the CD8alpha(-) and CD8alpha(+) subtypes. Furthermore, IL-23and IL-12-Ig exert biological activities on DC that are only in part overlapping. While both proteins induce IL-12 production from DC, only IL-23-Ig can act directly on CD8alpha(+) DC to promote immunogenic presentation of an otherwise tolerogenic tumor peptide. In addition, the in vitro effects of IL-23-Ig did not appear to require IL-12Rbeta2 or to be mediated by the production of IL-12. These data may establish IL-23 as a novel cytokine with major effects on APC.
Hereditary autoinflammatory disorders encompass manifold dysfunctions of innate immunity caused by mutations in genes coding for the main characters of the inflammatory scene: most of these ...conditions have an early onset, ranging from the first days of life to the first decades, and include hereditary periodic fevers, NLRP-related diseases, granulomatous and pyogenic syndromes, which are basically characterized by upturned inflammasome activity and overproduction of bioactive interleukin (IL)-1β and other proinflammatory cytokines. The discovery of a causative link between autoinflammation and IL-1β release has improved our understanding of the intimate mechanisms of innate immunity, and has likewise led to the identification of extraordinary treatments for many of these disorders.
Tertiary volcanic rocks in northwestern Firoozeh, Iran (the Meshkan triangular structural unit), constitute vast outcrops (up to 250 km
2
) of high-Mg basaltic andesites to dacites that are ...associated with high-Nb hawaiites and mugearites. Whole-rock
40
Ar/
39
Ar ages show a restricted range of 24.1 ± 0.4-22.9 ± 0.5 Ma for the volcanic rocks. The initial ratios of
87
Sr/
86
Sr and
143
Nd/
144
Nd vary from 0.703800 to 0.704256 and 0.512681 to 0.512877, respectively, in the high-Mg basaltic andesites-dacites. High-Th contents (up to 11 ppm) and Sr/Y values (27-100) and the isotopic composition of the subalkaline high-Mg basaltic andesites-dacites indicate derivation from a mantle modified by slab and sediment partial melts. Evidence such as reverse zoning and resorbed textures and high Ni and Cr contents in the evolved samples indicate that magma mixing with mafic melts and concurrent fractional crystallization lead to the compositional evolution of this series. The high-Nb hawaiites and mugearites, by contrast, have a sodic alkaline affinity and are silica undersaturated; they are also enriched in Nb (up to 47 ppm) and a wide range of incompatible trace elements, including LILE, LREE, and HFSE. Geochemistry and Sr-Nd isotopic compositions of the high-Nb hawaiites and mugearites suggest derivation from a mantle source affected by lower degrees of slab melts. Post-orogenic slab break-off is suggested to have prompted the asthenospheric upwelling that triggered partial melting in mantle metasomatized by slab-derived melts.
Murine plasmacytoid dendritic cells (pDCs) have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) function and mediate immunosuppression in specific settings; yet, the ...conditions of spontaneous versus induced activity have remained unclear. We have used maneuvers known to up-regulate IDO in different cell types and have examined the relative efficacy and mechanisms of the induced activity in splenic pDCs, namely, after specific receptor engagement by CTLA-4-Ig, CD200-Ig or CD28-Ig, the latter in combination with silenced expression of the suppressor of cytokine signaling 3 (SOCS3) gene. We found that pDCs (CD11c+ mPDCA-1+ 120G8+) do not express IDO and are not tolerogenic under basal conditions. B7-1 engagement by CTLA-4-Ig, CD200R1 engagement by CD200-Ig and B7-1/B7-2 engagement by CD28-Ig in SOCS3-deficient pDCs were each capable of initiating IDO-dependent tolerance via different mechanisms. IFN-γ was the major cytokine responsible for CTLA-4-Ig effects, and type I IFNs for those of CD200-Ig. Immunosuppression by CD28-Ig in the absence of SOCS3 required IFN-γ induction and IFN-like actions of IL-6. Therefore, although pDCs do not mediate IDO-dependent tolerance constitutively, multiple ligands and cytokines will contribute to the expression of a tolerogenic phenotype by pDCs in the mouse.
Pappophorum vaginatum is the most abundant C4 perennial grass desirable to livestock in rangelands of northeastern Patagonia, Argentina. We hypothesized that （1） defoliation reduce net primary ...productivity, and root length density and weight in the native species, and （2） root net primary productivity, and root length density and weight, are greater in P. vaginatum than in the other, less desirable, native species （i.e., Aristida spegazzinfi, A. subulata and Sporobolus cryptandrus）. Plants of all species were either exposed or not to a severe defoliation twice a year during two growing seasons. Root proliferation was measured using the cylinder method. Cylindrical, iron structures, wrapped up using nylon mesh, were buried diagonally from the periphery to the center on individual plants. These structures, initially filled with soil without any organic residue, were dug up from the soil on 25 April 2008, after two successive defoliations in mid-spring 2007. During the second growing season （2008-2009）, cylinders were destructively harvested on 4 April 2009, after one or two defoliations in mid- and/or late-spring, respectively. Roots grown into the cylinders were obtained after washing the soil manually. Defoliation during two successive years did reduce the study variables only after plants of all species were defoliated twice, which supported the first hypothesis. The greater root net primary productivity, root length den- sity and weight in P. vaginatum than in the other native species, in support of the second hypothesis, could help to explain its greater abundance in rangelands of Argentina.
The majority of the ∼143 ureilite meteorites are monomict (unbrecciated) ultramafic rocks, which represent the mantle (olivine+low-Ca pyroxene residues and less abundant cumulates) of a partially ...melted (∼25–30%), carbon-rich asteroid ⩾125
km in radius. Accumulated petrologic and geochemical studies of these meteorites have led to a picture of a ureilite parent body (UPB) that was stratified in
mg#, pyroxene abundance and pyroxene type, due to the pressure dependence of carbon redox control, and which preserved a pre-magmatic heterogeneity in Δ
17O. The absence, however, of ureilitic crustal rocks (i.e. basalts) in the meteorite record, leads to significant gaps in our knowledge of the geologic history of the UPB.
Ureilitic breccias provide considerable information that cannot be obtained from the monomict samples, and help to fill in those gaps. Fourteen ureilites are polymict breccias (at least three of which contain solar wind gases) that formed in a regolith. They contain a variety of clast types representing indigenous ureilitic lithologies not known among the monomict samples, as well as several types of non-indigenous impactor materials. In addition, one ureilite (FRO 93008) is a dimict breccia, consisting of two ultramafic lithologies that could not have formed in close proximity on the UPB.
Several feldspathic lithologies representing melts complementary to the monomict ureilite residues or cumulates have been recognized in polymict ureilites. From these lithologies we infer that melt extraction on the UPB was a rapid, fractional process in which trace element and oxygen isotopic equilibrium was not achieved. The majority of melts that reached the surface erupted explosively (due to high contents of CO/CO
2) and were lost into space. Thus, it is likely that the UPB never had an extensive basaltic crust. Melts generated at the shallowest depths and late fractionates, in which carbon had largely been consumed by reduction, were the most likely to have been preserved. Our sample of the UPB is limited to depths equivalent to ∼100 bars pressure or less, but minor augite-bearing feldspathic lithologies and related cumulates may represent melts derived from deeper.
In addition, we infer that the UPB was catastrophically disrupted, while still hot, by an impacting projectile. Meter-sized ejecta from this impact reaccreted into one or more daughter bodies, on which the brecciated ureilites formed. Ureilite meteorites are derived from these offspring, rather than from the UPB. The remnant of the original UPB may consist largely of olivine plus augite, and thus not resemble the majority of ureilites.
CTLA-4-Ig and CD28-Ig are both agonist ligands of B7 coreceptor molecules on mouse dendritic cells (DCs), yet they bias the downstream response in opposite directions, and CTLA-4-Ig promotes ...tolerance, whereas CD28-Ig favors the onset of immunity. Although B7 engagement by either ligand leads to a mixed cytokine response, a dominant IL-6 production in response to CD28-Ig prevents the IFN-gamma-driven induction of immunosuppressive tryptophan catabolism mediated by IDO. In the present study, we show that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFN-gamma signaling and IFN-gamma-like actions of IL-6. Thus, in the absence of SOCS3, CD28-Ig becomes immunosuppressive and mimics the action of CTLA-4-Ig on tryptophan catabolism.
Regulatory T (T(R)) cells manifest constitutive expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), but the function of CTLA-4 in mediating the regulatory function of T(R) cells is ...unclear. We show here that mouse CD4+CD25+ cells, either resting or induced to overexpress CTLA-4 by treatment with antibody to CD3, initiated tryptophan catabolism in dendritic cells through a CTLA-4-dependent mechanism. This process required B7 expression and cytokine production by the dendritic cells. In contrast, T(R) cells cultured in the presence of bacterial lipopolysaccharide induced tryptophan catabolism by dendritic cells in a CTLA-4-independent but cytokine-dependent way. Thus, regulation of immunosuppressive tryptophan catabolism in dendritic cells might represent a major mechanism of action of T(R) cells.
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