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Regulating Tregs
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RIIB receptor on DCs, leading to lower expression of costimulatory molecules on DCs and their eventual apoptosis. Without FGL2, Tregs cannot limit effector cell proliferation and autoimmunity results. Estrogen Suppresses Inflammation
Estrogens have anti-inflammatory properties and the production of inflammatory cytokines, such as TNF-
, increases after menopause. Inflammation can be suppressed through both estrogen receptors (ER), but action through ERβ causes suppression without proliferation of breast or uterine tissue. Cvoro et al. (p. 630
) have used microarray analysis to test whether estrogen acts by repressing proinflammatory cytokine gene transcription. The authors used TNF-- and estradiol-treated human osteosarcoma U2OS cells expressing ERβ to identify which genes estrogen repressed. Of the 49 genes activated by TNF-, 18 were suppressed by estradiol treatment and most of these were genes associated with inflammation, such as IL-6, MCP-1, and TNF-. Synthetic ligands specific for ERβ were used and it was found that ERβ was more effective than ER at suppressing TNF- induced cytokine gene expression when tested in U2OS cells expressing either ER or ERβ. The mechanism of ERβ transcriptional suppression was found to involve recruitment of the steroid receptor coactivator 2 (SRC-2). ERβ was also able to suppress LPS-induced transcription of TNF-, MCP-1, and CSF-2 in PBMCs. With its anti-inflammatory capabilities and lack of proliferative effect, ERβ provides a potentially attractive therapeutic target for modulating inflammation.
MRSA Evades Death
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) typically infects otherwise healthy individuals. A dramatic increase in the incidence of infections has brought this bacterium to the attention of the popular press. CA-MRSA is more virulent than other strains of MRSA such as identified hospital-associated strains, in part through resistance to neutrophil killing. Palazzolo-Ballance et al. (p. 500
) determined that MRSA evades killing by up-regulating the transcription of genes important for survival upon exposure to the neutrophilic antimicrobial products HOCl, H2O2, and azurophilic granule proteins. Exposure to azurophilic granule proteins increased the production of mRNAs encoding several hemolysin and toxin products, explaining the enhanced ability of CA-MRSA to lyse neutrophils. Bacterial genes involved in stress responses were up-regulated after exposure to any of the anti-microbial compounds, but H2O2 specifically increased transcripts related to heme/iron uptake such the as iron-regulated surface determinants (isd) isdA and isdB. A strain deficient in these transcripts, 
isdAB, was more susceptible than wild type to killing by neutrophils, although this could be reversed by pretreatment with an NADPH oxidase inhibitor. Because phagocytosis of both the wild-type strain and the mutant strain was similar, killing was determined to be due to oxidant susceptibility. The authors thus conclude that CA-MRSA has several mechanisms effective for evading neutrophil killing, including direct lysis and oxidant resistance.
Stabilizing IL-2
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Why Colds Make Asthma Worse
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and IL-12 in the bronchial alveolar lavage (BAL) fluid of OVA-exposed rats when compared with OVA exposure alone. Direct administration of PGD2 increased lung eosinophilia in OVA-exposed rats but not in animals treated with PBS. This effect could be nearly eliminated by ramatroban, a dual receptor antagonist for the PGD2 receptor (CRTH2) and the thromboxane A2 receptor (TP), but not by antagonists to TP receptors alone. Poly I:C had no effect on allergen-induced airway eosinophilia in CRTH2-deficient mice, with CRTH2–/– and wild-type mice showing similar levels of airway eosinophils after allergen exposure. The authors have provided an elegant explanation of how respiratory RNA viruses make asthma worse through the production of PGD2 and point to CRTH2 as a therapeutic target to ameliorate this condition. ATRA Accelerates B Lymphopoiesis
All trans retinoic acid (ATRA) is known to affect hemopoietic stem cells (HSCs), specifically by promoting maturation in the myeloid lineage. Chen et al. (p. 138 ) have expanded on this knowledge to show that ATRA stimulates HSC progression to progenitor cells that mature into B cells and a subset of myeloid cells. Mice that were treated with ATRA had larger spleens when compared with controls, and this increase was due to increased B cell numbers as T and NK cell numbers were unchanged. CD11c+CD11b+ myeloid dendritic cells were also elevated in the spleens of ATRA-treated mice; however, the total number of CD11b+ cells remained the same, indicating a preferential expansion of this subset. In the bone marrow, HSC numbers were normal, the numbers of early lymphoid progenitors (ELPs) and prolymphocytes were significantly reduced, and pre-B cells were decreased. However, numbers of bone marrow CD19+B220+ and CD45R/B220Lo IgM+ cells increased, indicating that ATRA accelerated the differentiation of progenitors into B cells. In vitro, ATRA was able to reduce maturation time of ELPs to B cell progenitors from 10 days to 7. This work enhances the understanding of how ATRA affects B cell hemopoiesis and development, a matter of particular interest because retinoids are used therapeutically and vitamin A deficiency is linked with immunodeficiency.
IL-15 in SIV
Interleukin-15, a proinflammatory cytokine, has been shown to increase the proliferation of CD8+ T cells and NK cells and enhance lymphocyte homing to the peripheral lymph nodes (LNs). Mueller et al. (p. 350 ) looked at the action of this cytokine in SIV infection. Macaques acutely infected with SIV were treated with IL-15, resulting in a significant increase in SIV-specific CD8+ T and NK cells that correlated with peak viremia. However, the viral set point at week 20 after infection was 3 logs higher in IL-15 treated animals when compared with controls and led to accelerated disease. This may in part be due to an increase in the numbers of Ki-67+ CD4+ T cells in IL-15 treated animals, thereby creating a larger target population for SIV infection. The anti-SIV Ab response was reduced in animals that received IL-15. The lymph nodes of IL-15-treated macaques had fewer SIV-infected cells at peak viremia compared with untreated SIV-infected animals; however, this was reversed when the viral set point was reached. While SIV-specific CD8+T and NK cells were increased by treatment with IL-15, the peak viremia in acute infection remained the same but the viral set point was increased. These data show that although IL-15 treatment increases the number of virus-specific CD8+ T cells early in disease, it does not protect against later viremia and increases the overall viral burden.
Mouse Model of Melanoma
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1-2 domains of HLA-A2 linked to the H2-Dd 3 domain) were used to look at CD8+ T cell responses to previously identified human melanoma Ags. Eighty-five percent of metallothionein (MT)-ret/AAD mice developed spontaneous tumors at 4 mo and anti-tumor T cell responses were found in all tumor-bearing mice. In vitro, CD8+ T cells from the spleens of tumor-bearing mice produced IFN- in response to B16.F10 melanoma cells expressing AAD (B16AAD) but not to B16 melanoma cells without AAD, indicating that the anti-tumor response was HLA-A2 restricted. The authors showed that each cutaneous tumor had a unique melanoma differentiation Ag (MDA) profile, but this did not affect the tumor’s ability to elicit Ag-specific CD8+ T cell responses in vitro. In contrast, visceral metastases had reduced expression of AAD and MDAs and thus were poorly antigenic in culture. MT-ret/AAD mice were treated with anti-CD8 depletion Ab at 8–11 days of age, before the formation of tumors, to see whether CD8+ T cells controlled tumor development. Depletion of CD8+ T cells increased visceral metastasis and substantially shortened life span, with >70% of treated mice dead at 6 mo compared with >90% of control mice still alive. Thus CD8+ T cells did not change the onset of disease but substantially delayed mortality and the spread of visceral metastases. Summaries written by Kira R. Gantt, Ph.D.
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