| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Role of apolipoprotein E in inflammation
|
and fibrinogen, in apoE–/– livers compared with controls. No difference in liver macrophage populations was seen in wild-type mice fed a high cholesterol diet or in mice lacking the low-density lipoprotein receptor. The authors conclude that apoE is required for efficient clearance of apoptotic bodies in tissues, and that its absence changes macrophage population dynamics and results in a systemic proinflammatory condition independent of its role in lipoprotein metabolism. Stabilizing telomeres in HIV-1+CD8+ T cells
Human immunodeficiency virus-1-infected CD8+ T cells, which undergo repeated antigenic stimulation, have shortened telomeres. Genetic manipulation of hTERT, the catalytic subunit of human telomerase that prevents senescence and increases proliferative potential in several cell types, offers the possibility of altering CD8+ T cell replicative senescence. Dagarag et al. (p. 6303
) found that CD8+ T cells from HIV-1-infected individuals transfected with an hTERT expression vector underwent nearly three times the number of population doublings (p.d.) in vitro compared with vector-transfected cells. The rate of telomere shortening in hTERT-expressing cells was slower than in controls and stabilized by 45 p.d. Markers of replicative senescence—elevated levels of two cyclin-dependent kinase inhibitors and loss of CD28 expression on CD8+ T cells—were reduced in hTERT cells. Viral replication also was reduced in HIV-1-infected cells cocultured with hTERT cells. Transduction of HIV-1-infected CD8+ T cells with hTERT at an early stage when most cells express CD28 led to continued proliferation even after loss of CD28; HIV-1-infected T cells transduced later, and uninfected T cells, stopped dividing much earlier. IFN-
and TNF- production in response to viral peptide-specific stimulation continued for more p.d. in hTERT cells. However, hTERT expression did not prevent the loss of HIV-1-specific CTL activity at late p.d. The data show that stable hTERT expression in HIV-1-specific CD8+ T cells prolongs antiviral activity and longevity of viral peptide-reactive cells and offers a new strategy for HIV-1 therapy.
Schistosome worms protect against anaphylaxis
In accordance with the Hygiene Hypothesis, schistosome infection in humans reduces allergic responses. Although several cytokines are up-regulated in worm-infected animals, it is not clear what role each cytokine plays. Mangan et al. (p. 6346
) found that mice infected with Schistosoma mansoni worms were completely protected in a model of systemic anaphylaxis induced by penicillin V (Pen)-BSA challenge of Pen-OVA sensitized mice; 10–20% of uninfected mice died and worm-plus-egg-infected mice had only slight anaphylaxis. Sera from uninfected or infected sensitized animals did not confer protection in naive mice, and passively transferred IgG1 or IgE specific for TNP did not reduce protection to TNP-induced anaphylaxis in worm-infected mice. Depletion of CD4+CD25+ T cells or macrophages did not reduce worm protection. Worm-infected sensitized mice injected i.p. with anti-IL-10R mAb or anti-IgM Ab were highly susceptible to anaphylaxis, as were worm-infected IL-10–/– mice; injection of anti-TGF-
mAb had no effect. Sensitized mice receiving wild-type B cells incubated in vitro with live worms rapidly recovered from anaphylaxis, but animals receiving IL-10–/– B cells incubated in vitro with worms had severe and fatal anaphylaxis. Prior injection of IL-4 into sensitized mice exacerbated anaphylaxis after Ag challenge; injection of IL-10, with or without IL-4, was protective. Transfer of in vitro worm-modulated B cells from mice deficient in four cytokines, including IL-4, completely protected sensitized recipients from anaphylaxis. The authors conclude that S. mansoni worm infection of mice prevents anaphylaxis via a B cell- and IL-10-dependent mechanism.
CD63 is an inducible T cell costimulatory molecule
|
, and induction of survival genes than cells coincubated with control mAbs. Anti-CD63 also enhanced T cell proliferation and IL-2 production induced by anti-CD28 mAb or by low amounts of anti-CD3 plus anti-CD28. T cells activated with anti-CD3 plus anti-CD63 had a stronger response to secondary stimulation with a variety of Abs or APCs than T cells activated with anti-CD3 plus anti-CD28. The authors delineate CD63 as an activation-induced costimulatory molecule on T cells capable of enhancing responsiveness of cells stimulated by other mechanisms. Apoptotic neutrophils and macrophage activation
|
and lower amounts of TGF- than macrophages ingesting UV-induced (i.e., spontaneous) apoptotic neutrophils or than macrophages incubated with medium. FcR1 expression on macrophages was increased following uptake of only infected apoptotic neutrophils. No TNF- was produced by macrophages exposed to bacteria alone, to neutrophils incubated with formalin-fixed bacteria, or to neutrophils irradiated after incubation with fixed bacteria; addition of LPS to apoptotic neutrophils marginally increased TNF- production by macrophages. Increased expression of heat shock proteins HSP60 and HSP70 was seen by immunoblot analysis in pathogen-induced, but not in UV-induced, apoptotic neutrophils. Macrophages that ingested heat-exposed neutrophils produced high levels of TNF-, as did macrophages treated with LPS and purified recombinant HSP60 or HSP70. Neutrophils treated with cycloheximide before exposure to pathogen or heat lost expression of the HSPs and induced lower TNF- production in ingesting macrophages. The data indicate that pathogen-induced apoptotic neutrophils activate, via HSPs, macrophages that ingest them, whereas UV-induced apoptotic neutrophils do not. Monocyte-NK cell interactions in inflammation
Two subsets of NK cells are found in peripheral blood. Most are CD56dim; 
10% are CD56bright. The dominant subset in healthy lymph nodes and in synovial fluid of patients with rheumatoid arthritis is CD56bright; however, the role CD56bright NK cells might play in development or maintenance of inflammation is unknown. Dalbeth et al. (p. 6418
) isolated NK cells from peripheral blood and inflamed sites of patients with a variety of inflammatory diseases. CD56dim NK cells predominated in peripheral blood, whereas CD56bright NK cells that also expressed CD69 predominated at inflamed sites. A large proportion of NK cells from inflamed sites produced IFN- when cultured with low concentrations of IL-12 and IL-18, whereas few NK cells from peripheral blood did. Higher production of TNF- by monocytes occurred in the presence of the two cytokines and CD56bright NK cells than in the presence of the cytokines and CD56dim NK cells. The converse experiment gave similar results, i.e., addition of monocytes and cytokines induced CD56bright NK cells to release higher levels of IFN- than similarly treated CD56dim NK cells. The source of monocytes and NK cells—from healthy individuals or from patients—did not change the responses; separating monocyte and NK cell populations using a transwell diminished all responses. The authors show that CD56bright NK cells accumulate at sites of inflammation where, in the presence of cytokines, they directly interact with monocytes in a reciprocal activatory fashion.
Biological role of CLAN
|
, but not with PMA, CSF-1, or IFN-. A higher level of IL-1 was released from LPS- or peptidoglycan (PGN)-treated monocytes stably transfected with a CLAN expression vector than from vector controls; IL-1 production was reduced in LPS- or PGN-treated monocytes expressing a construct encoding a CLAN-specific RNA-interference hairpin sequence. CLAN-expressing cells preincubated with inhibitors of proinflammatory caspases did not release IL-1 after LPS or PGN treatment. Macrophages differentiated from the transfected cells had overexpressed IL-1 after infection with Salmonella but not after infection with other pathogens that do not reside in intracellular vacuoles; caspase inhibitors blocked the IL-1 response. Intracellular levels of Salmonella were reduced in macrophages overexpressing CLAN compared with controls. However, higher macrophage death was seen at very high multiplicity of infection, and only a broad-spectrum caspase inhibitor prevented the cell death. The data show that CLAN modulates human macrophage responses to bacterial infections by a caspase-1-dependent secretion of IL-1 and by a caspase-1-independent antibacterial effect. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
