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Control of cutaneous inflammation
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in the basal layer of the epidermis and the outer root sheath of the hair follicle. Application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the skin resulted in epidermal apoptosis and an influx of neutrophils in the transgenic, but not wild-type, mice within 6 h. By 12 h, a severe but transient inflammatory response developed only in the skin of transgenic animals. Cultured keratinocytes from transgenic mice, but not those from wild-type animals, became apoptotic after in vitro treatment with TPA. Cell death was blocked by pretreatment of the transgenic keratinocytes with a PKC inhibitor before addition of TPA. TPA treatment of keratinocytes from mice bitransgenic for PCK and an AP-1-dependent reporter construct led to a high level of reporter activity that was blocked by transduction of an AP-1 dominant negative construct before exposure of the cells to TPA. However, blockage of AP-1 did not prevent TPA-induced inflammation in vivo when the bitransgenic mice were made triple transgenic with the AP-1 inhibitor gene. The data show that PKC-mediated apoptosis is dependent on AP-1 but that inflammation is independent of AP-1. Targeted therapy for pulmonary fibrosis
Patients suffering from severe forms of idiopathic interstitial pneumonia, such as usual interstitial pneumonia (UIP), often fail to respond to current steroid and immunosuppressive therapies. The challenge in reducing the pulmonary fibrosis that accompanies UIP is to establish specific targets for treatment. Jakubzick et al. (p. 2684
) examined the expression of IL-4 and IL-13 and their receptor subunits in the lungs of mice at various times after challenge with the chemotherapeutic drug bleomycin. Expression of IL-4 and IL-13 mRNA and protein reached a peak 28 days after intratracheal challenge of the animals with bleomycin. Similarly, IL-4R and IL-13R1 mRNA and IL-4R and IL-13R2 protein levels peaked at 21–28 days after challenge and were detected predominantly in macrophages and mononuclear cells. Mice given an intranasal bolus of a human IL-13 chimeric molecule containing a mutated form of Pseudomonas exotoxin (IL13-PE) from days 21–28 after bleomycin challenge had reduced lung fibrosis and inflammation compared with saline-treated, bleomycin-challenged controls. Lungs of IL13-PE-treated, but not saline-treated, mice had reduced levels of several profibrotic cytokines and chemokines, reduced levels of monocytes and NK cells, reduced mRNA and protein expression of IL-4R and IL-13R1 subunits, but increased expression of IL-13R2 at day 28. The authors suggest that IL13-PE selectively targeted IL-13R-expressing cells in pulmonary fibrosis via the 2 subunit.
IL-12 and dendritic cells in tumor therapy
One approach to effective tumor immunotherapy is to use dendritic cells (DC) to sensitize T cells against specific tumor Ags. Of critical importance is the need to sensitize T cells to recognize the specific Ags on the tumor cells and not just in the context of the APC. Xu et al. (p. 2251
) evaluated DC1 and DC2 that skew T cell responses toward a Th1 or Th2 type, respectively. They generated DC1 or DC2 from normal human monocytes using two different cocktails of factors in a rapid (2-day) culture technique. The resulting cell populations were phenotypically similar but had markedly different cytokine and chemokine expression profiles. In particular, DC1 secreted high levels of IL-12 compared with DC2. DC1 that were pulsed with tumor Ags sensitized normal human CD8+ T cells to recognize and lyse cognate tumor cells in vitro at a level that was greatly enhanced when compared with CD8+ T cells that were sensitized by DC2 pulsed with the same Ags. IL-12, but not control, Ab blocked the DC1-induced tumor cell recognition, whereas the addition of recombinant IL-12 to cocultures of DC2 and T cells led to a sensitization level comparable to that seen with DC1. CD8
heterodimer vs CD8 homodimer expression was significantly higher on T cells sensitized by DC1 compared with T cells sensitized by DC2. The authors conclude that priming T cells in the presence of IL-12 increases the functional avidity of anti-tumor T cells through enhanced expression of CD8.
Heparan sulfate is a pre-BCR ligand
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5. This complex then associates with the signal transducer, Ig, to form the pre-B cell receptor (pre-BCR). However, the ligand required for signaling and B cell proliferation and the nature of its interaction with the pre-BCR are unknown. Bradl et al. (p. 2338
) had previously detected an interaction between a soluble murine pre-BCR and murine stromal cells. To establish the basis for the interaction, they mutated the 5 chain by deleting the N-terminal unique tail. The mutant 5, in association with a wild-type VpreB chain, was unable to bind to stromal cells. However, a mutant VpreB, deleted in its C-terminal unique tail, was able to bind to stromal cells in association with wild-type or mutant 5 chain. The binding of the pre-BCR to the stromal cells was blocked if heparin was present during the binding reaction or if the stromal cells were pretreated with heparitinase. Soluble pre-BCR bound to heparin-Sepharose columns. Inhibition of heparin sulfation by incubation of stromal cells with sodium chlorate greatly reduced pre-BCR binding, thus identifying heparan sulfate as the pre-BCR ligand on the cell surface. The authors determined that galectin-1, a known ligand for human pre-BCR, was not involved in the binding of the murine pre-BCR to mouse or human stromal cells. Immune response to West Nile virus
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and 
T cells are crucial in the early response of C57BL/6 (B6) mice to the virus. One-hundred percent of TCR-/- and 90% of TCR-/- mice died within 2 wk of WN virus infection, in contrast with only 25% of wild-type B6 mice. Whereas both mutant strains of mice had increased levels of virus in their blood, spleen, and brain compared with wild-type mice, the levels were significantly higher in TCR-/- mice. Expansion of T cells, a source of IFN-, was greater than that of T cells in the spleen and peritoneal cavity of B6 mice following virus infection. Mice deficient in IFN- had higher death rates after virus infection than B6 controls, and mice doubly deficient for IFN- and T cells had elevated viral loads compared with TCR-/- mice. IFN- and perforin levels were greatly reduced in the splenocytes of TCR-/- mice infected with WN virus. Transfer of TCR-/- splenocytes into virus-infected TCR-/- mice increased the survival rate to 40% compared with a 60% survival of infected wild-type mice, whereas transfer of TCR-/- IFN- -/- splenocytes into infected TCR-/- mice resulted in 100% mortality. The authors conclude that an early T cell response mediated by IFN- is important in surviving infection by WN virus. Apoptosis and innate immunity
Clearance of dying cells by macrophages occurs at sites of infection, inflammation or tissue remodeling. However, the role that apoptotic cell death plays in innate immunity is unclear. Lucas et al. (p. 2610
) examined the regulation of chemokine and cytokine production in mouse macrophages exposed to apoptotic human neutrophils and/or LPS. Macrophages doubly stimulated by exposure to apoptotic cells and LPS released TNF- and macrophage-inflammatory protein 1 (MIP-1) over the first 2–4 h, earlier than cells stimulated with LPS alone. By 24 h, TNF- production was undetectable, whereas the MIP-1 level remained high in the doubly stimulated cells. The late suppression of TNF- production did not occur in the presence of IFN-. A functional macrophage TLR4 was essential for the response to the combination of apoptotic cells and LPS. Whereas stimulation of macrophages by apoptotic cells alone did not result in the production of pro-inflammatory factors, it did result in the production of the anti-inflammatory cytokine TGF-1 between 8 and 24 h. The authors suggest that the combination of apoptotic cell death and innate immune stimuli promote proinflammatory cytokine production and, possibly, neutrophil recruitment. These effects appear to be mediated by an early production of TNF- that diminishes at a time of increasing TGF-1 production.
Arachidonic acid and neutrophils
Down-regulation of TNFR expression on the surface of neutrophils is mediated by several TNFR agonists and contributes to resolution of the inflammatory response. Arachidonic acid (AA) is released from membrane phospholipids during inflammation and is known to stimulate neutrophils. However, there is no information about a direct effect of AA on TNFR expression in neutrophils. Moghaddami et al. (p. 2616 ) found that AA increased TNFR1 and TNFR2 expression on human neutrophils, but not other cell types, by 8-fold over normal levels. Maximum increases occurred by 30 min at a concentration of 30 µM and were accompanied by increased superoxide production in response to TNF. In contrast, two other fatty acids reduced the expression of both receptors. Treatment of neutrophils with AA reduced the release of soluble TNFR and prevented its proteolytic cleavage by an agonist. Alteration of AA by addition of a hydroperoxy moiety or conversion to the methyl form resulted in the loss of the ability to stimulate TNFR expression. Likewise, inhibitors of several cellular kinases and a phospholipase resulted in the loss of the stimulatory activity of AA with a greater reduction seen for TNFR1 expression compared with TNFR2. The ability of AA to up-regulate TNFR suggests that AA can synergize with TNF to propagate inflammation.
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
5 and Stroma Cell-Associated Heparan Sulfate
-Producing T Cells Help Control Murine West Nile Virus Infection
Induces Keratinocyte Apoptosis and Intraepidermal Inflammation by Independent Signaling Pathways
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