Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1alpha, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12-24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.
The contribution of environmental factors is important as we consider reasons that underlie differential susceptibility to influenza virus. Aryl hydrocarbon receptor (AhR) activation by the pollutant dioxin during influenza virus infection decreases survival, which correlates with a 4-fold increase in pulmonary IFN-γ levels. We report here that the majority of IFN-γ-producing cells in the lung are neutrophils and macrophages not lymphocytes, and elevated IFN-γ is associated with increased pulmonary inducible NO synthase (iNOS) levels. Moreover, we show that even in the absence of dioxin, infection with influenza virus elicits IFN-γ production by B cells, γδ T cells, CD11c+ cells, macrophages and neutrophils, as well as CD3+ and NK1.1+ cells in the lung. Bone marrow chimeric mice reveal that AhR-mediated events external to hemopoietic cells direct dioxin-enhanced IFN-γ production. We also show that AhR-mediated increases in IFN-γ are dependent upon iNOS, but elevated iNOS in lung epithelial cells is not driven by AhR-dependent signals from bone marrow-derived cells. Thus, the lung contains important targets of AhR regulation, which likely influence a novel iNOS-mediated mechanism that controls IFN-γ production by phagocytic cells. This suggests that AhR activation changes the response of lung parenchymal cells, such that regulatory pathways in the lung are cued to respond inappropriately during infection. These findings also imply that environmental factors may contribute to differential susceptibility to influenza virus and other respiratory pathogens.
Prostate specific membrane antigen (PSMA) is a 100 kDa glycoprotein that is located on the plasma cell membrane of prostate cancer cells. 1,2 PSMA is an enzyme with 3 known activities: folate hydrolase, 3 NAALADase 4 and dipeptidyl peptidase IV. 5 PSMA is expressed in primary and metastatic prostate cancers, 6,7 normal prostate epithelium 9 as well as tumor-associated neovasculature. 10 High expression of PSMA protein was demonstrated in poorly differentiated and advanced prostate cancers, 7 and after androgendeprivation therapy. 11 The plasma membrane orientation and expression in more aggressive prostate cancer makes PSMA an attractive therapeutic and diagnostic target for prostate cancer. This potential was exemplified by the recent FDA approval of an 111 In-labeled PSMA monoclonal antibody (Prostascint ) for diagnostic imaging of prostate cancer.The first reported splicing variant of PSMA was identified from RT-PCR studies of normal prostate tissue. 12 This variant, PSMЈ, transcribes from the same promoter as PSMA, however, bases 114 -379 of the genomic PSMA sequence are removed by alternative splicing. Translation of the PSMЈ gene begins at a novel translation start codon producing a 95 kDa protein that lacks the intracellular and transmembrane domains. LNCaP cell fractionation studies demonstrated that PSMЈ localized within the cytoplasm. 13 Quantitation of PSMA and PSMЈ mRNA was achieved by an RNase protection assay using probes that discriminated between each mRNA. 12 A tumor index was described (PSMA:PSMЈ ratio) to compare the relative expression of each mRNA. The PSMA:PSMЈ ratio increased with progression from the normal to cancerous state in 9 prostatic tissues studied.Using 5Ј RACE of the PSMA gene, O'Keefe et al. 14 discovered 2 additional alternatively spliced variants of PSMA. The first, PSM-C, begins transcription at the same nucleotides as PSMA and PSMЈ. PSM-C contains the same splice donor site as PSMЈ (nt 114) but uses an alternative splice acceptor site located within intron one of the PSMA gene. 14 Transcription of this gene produces an mRNA that contains an additional 133 nucleotides (nucleotides 3270 -3402 of the genomic PSMA sequence) compared to PSMЈ (Fig. 1). PSM-C uses the same translation start codon as PSMЈ and would therefore produce a protein that is identical to PSMЈ. 14 The second novel PSMA splice variant, PSM-D, uses the same splice donor site as PSMЈ and a unique splice acceptor site located within intron one, including another novel exon that is from nucleotides 4289 -4389 of the genomic PSMA sequence. 14 The putative translation of this protein shows a novel translation start codon within this new exon followed by 24 novel amino acids and the rest of the PSMA protein in frame. 14 Our present study developed a real-time, quantitative PCR assay to measure transcripts of PSMA and 3 alternatively spliced variants of PSMA in specimens of normal, benign, primary and metastatic prostate tissues from 72 patients. This assay allowed for sensitive determination of PSMA mRNA in clinic...
There is growing evidence that neutrophils influence host resistance during influenza virus infection; however, factors that regulate neutrophil migration to the lung during viral infection are unclear. Activation of the aryl hydrocarbon receptor (AhR) by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in an increased number of neutrophils in the lung after influenza virus infection. The mechanism of AhR-mediated neutrophilia does not involve elevated levels of soluble neutrophil chemoattractants, upregulated adhesion molecules on pulmonary neutrophils, delayed neutrophil apoptosis, or increased vascular damage. In this study, we determined whether AhR activation increases neutrophil numbers systemically or only in the infected lung, and whether AhR-regulated events within the hematopoietic system underlie the dioxin-induced increase in pulmonary neutrophils observed during influenza virus infection. We report here that AhR activation does not increase neutrophil numbers systemically or increase neutrophil production in hematopoietic tissue, suggesting that the elevated number of neutrophils is restricted to the site of antigen challenge. The generation of CD45.2AhR-/--->CD45.1AhR+/+ bone marrow chimeric mice demonstrates that even when hematopoietic cells lack the AhR, TCDD treatment still results in twice as many pulmonary neutrophils compared with control-treated, infected CD45.2AhR-/--->CD45.1AhR+/+ chimeric mice. This finding reveals that AhR-mediated events extrinsic to bone marrow-derived cells affect the directional migration of neutrophils to the infected lung. These results suggest that the lung contains important and heretofore overlooked targets of AhR regulation, unveiling a novel mechanism for controlling neutrophil recruitment to the infected lung.
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