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1.
Ann Allergy Asthma Immunol ; 107(2): 145-53, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21802023

ABSTRACT

BACKGROUND: Asthma is a chronic airway inflammatory disease that is associated with a large influx of inflammatory cells. Several chemokines and chemokine receptors play critical roles in the development of allergic airway inflammation. OBJECTIVE: Because polarized human T(H)2 cells express a functional CXCR3 chemokine receptor, we evaluated the effects of a selective CXCR3 inhibitor in a mouse model of allergic airway disease. METHODS: Ovalbumin-specific CD8(+) T effector cells were generated from OT-1 mice in the presence of interleukin 2. The activity of a CXCR3 inhibitor was examined in vitro by monitoring Ca(2+) influx after receptor ligation. In vivo, the activity was assessed in sensitized and challenged mice by monitoring airway function, inflammatory parameters, including cellular infiltrates and cytokines in the bronchoalveolar lavage fluid. RESULTS: Approximately 40% of CD8(+) T effector cells expressed the CXCR3 receptor. In vitro, CXCR3 antagonism reduced Ca(2+) influx after receptor engagement. In contrast, the CXCR3 antagonist had little to no effect on airway function or inflammatory parameters despite adequate exposure levels. CONCLUSIONS: CXCR3 antagonism did not prevent allergen-induced airway hyperresponsiveness or airway inflammation in a mouse allergy model despite having activity in in vitro functional assays.


Subject(s)
Immunotherapy , Pneumonia/drug therapy , Pneumonia/physiopathology , Receptors, CXCR3/antagonists & inhibitors , Th2 Cells/metabolism , Animals , Asthma/drug therapy , Asthma/immunology , Cell Movement/drug effects , Cell Movement/immunology , Disease Models, Animal , Disease Progression , Female , Humans , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Mice, Transgenic , Molecular Targeted Therapy , Pneumonia/chemically induced , Pneumonia/immunology , Respiratory Function Tests , Th2 Cells/immunology
2.
PPAR Res ; 2010: 970164, 2010.
Article in English | MEDLINE | ID: mdl-20445733

ABSTRACT

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/ 0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.

3.
Biochem Biophys Res Commun ; 378(4): 777-82, 2009 Jan 23.
Article in English | MEDLINE | ID: mdl-19070594

ABSTRACT

Neuromedin U (Nmu) is a neuropeptide expressed primarily in the gastrointestinal tract and central nervous system. Previous reports have identified two G protein-coupled receptors (designated Nmur1 and Nmur2) that bind Nmu. Recent reports suggest that Nmu mediates immune responses involving mast cells, and Nmur1 has been proposed to mediate these responses. In this study, we generated mice with an Nmur1 deletion and then profiled the responses of these mice in a cutaneous inflammation model utilizing complete Freund's adjuvant (CFA). We report here that mice lacking Nmur1 had normal inflammation responses with moderate changes in serum cytokines compared to Nmur1(+/+) littermates. Although differences in IL-6 were observed in mice lacking Nmu peptide, these mice exhibited a normal response to CFA. Our data argues against a major role for Nmur1 in mediating the reported inflammatory functions of NmU.


Subject(s)
Dermatitis/immunology , Receptors, Neurotransmitter/physiology , Animals , Cytokines/blood , Dermatitis/genetics , Freund's Adjuvant/immunology , Freund's Adjuvant/pharmacology , Gene Deletion , Mice , Mice, Knockout , Receptors, Neurotransmitter/genetics
4.
J Biol Chem ; 282(16): 11658-66, 2007 Apr 20.
Article in English | MEDLINE | ID: mdl-17197447

ABSTRACT

Functional interleuin-8 (IL-8) receptors (IL-8RA and IL-8RB: CXCR1 and CXCR2, respectively) have been described in human, monkey, dog, rabbit, and guinea pig. Although three IL-8R homologues have been found in rat, only one of these, rat CXCR2, appears to be functional based on responsiveness to ligands. Similarly, CXC chemokines induce biological responses through the murine homolog of CXCR2, but the identification of functional rodent CXCR1 homologues has remained elusive. We have identified and characterized the mouse CXCR1 homologue (mCXCR1). Murine CXCR1 shares 68 and 88% amino acid identity with its human and rat counterparts, respectively. Similar to the tissue distribution pattern of rat CXCR1, we found murine CXCR1 mRNA expression predominantly in lung, stomach, bone marrow, and leukocyte-rich tissues. In contrast to previous reports, we determined that mCXCR1 is a functional receptor. We show predominant engagement of this receptor by mouse GCP-2/CXCL6, human GCP-2, and IL-8/CXCL8 by binding, stimulation of GTPgammaS exchange, and chemotaxis of mCXCR1-transfected cells. Furthermore, murine CXCR1 is not responsive to the human CXCR2 ligands ENA-78/CXCL5, NAP-2/CXCL7, GRO-alpha, -beta, -gamma/CXCL1-3, or rat CINC-1-3. In addition, we show concomitant elevation of mCXCR1 and its proposed major ligand, GCP-2, positively correlated with paw swelling in murine collagen-induced arthritis. This report represents the first description of a functional CXCR1-like receptor in rodents.


Subject(s)
Chemokines, CXC/metabolism , Interleukin-8/metabolism , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/physiology , Amino Acid Sequence , Animals , Arthritis, Experimental/metabolism , Chemokine CXCL6 , Cloning, Molecular , Collagen/metabolism , Disease Models, Animal , Humans , Mice , Molecular Sequence Data , RNA, Messenger/metabolism , Rats , Sequence Homology, Amino Acid
5.
J Immunol ; 174(6): 3686-94, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15749907

ABSTRACT

Kaposi's sarcoma (KS)-associated herpesvirus or human herpes virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpesvirus/human herpes virus 8 open reading frame 74 encodes a constitutively active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach for the treatment of KS.


Subject(s)
Herpesvirus 8, Human/immunology , Herpesvirus 8, Human/pathogenicity , Receptors, Chemokine/physiology , Sarcoma, Kaposi/etiology , Viral Proteins/physiology , Animals , Becaplermin , Disease Models, Animal , Doxycycline/pharmacology , Gene Expression/drug effects , Herpesvirus 8, Human/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Neovascularization, Pathologic , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Placenta Growth Factor , Platelet-Derived Growth Factor/metabolism , Pregnancy Proteins/metabolism , Proto-Oncogene Proteins c-sis , Receptors, Chemokine/genetics , Sarcoma, Kaposi/blood supply , Sarcoma, Kaposi/immunology , Sarcoma, Kaposi/pathology , Viral Proteins/genetics
6.
J Immunol ; 170(6): 2843-52, 2003 Mar 15.
Article in English | MEDLINE | ID: mdl-12626534

ABSTRACT

The analysis of the development and function of distinct subsets of murine dendritic cells (DC) has been hampered by the limited number of these cells in vivo. To circumvent this limitation we have developed a conditional transgenic mouse model for producing large numbers of DC. We used the tetracycline-inducible system to conditionally express murine Flt3 ligand (FL), a potent hemopoietic growth factor that promotes the differentiation and mobilization of DC. Acute treatment (96 h) of the transgenic animals with the tetracycline analog doxycycline (DOX) promoted an approximately 200-fold increase in serum levels of FL without affecting the number of circulating DC. However, within 1 wk of DOX treatment, the relative number of DC in peripheral blood increased from approximately 8 to approximately 40%. Interestingly, both the levels of FL and the number of DC remained elevated for at least 9 mo with continual DOX treatment. Chronic treatment of the mice with DOX led to dramatic increases in the number of DC in multiple tissues without any apparent pathological consequences. Most DC populations were expanded, including immature and mature DC, myeloid (CD11c(+)CD11b(+)CD8a(-)), lymphoid (CD11c(+)CD11b(-)CD8a(+)), and the recently defined plasmacytoid (pDC) subsets. Finally, transplantation of BM from green fluorescent protein-expressing mice into lethally irradiated transgenic mice followed by subsequent DOX treatment led to expansion of green fluorescent protein-labeled DC. The transgenic mice described here should thus provide a readily available source of multiple DC subsets and should facilitate the analysis of their role in homeostasis and disease.


Subject(s)
Dendritic Cells/cytology , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Animals , CD11c Antigen/biosynthesis , CD11c Antigen/blood , Cell Division/drug effects , Cell Division/genetics , Cell Division/immunology , Cell Movement/drug effects , Cell Movement/genetics , Cell Movement/immunology , Crosses, Genetic , Dendritic Cells/metabolism , Doxycycline/pharmacology , Gene Expression Regulation/drug effects , Green Fluorescent Proteins , Immunophenotyping , Ligands , Luminescent Proteins/biosynthesis , Luminescent Proteins/genetics , Lymphocyte Activation/genetics , Lymphocyte Subsets/cytology , Lymphocyte Subsets/immunology , Membrane Proteins/blood , Membrane Proteins/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Myeloid Cells/cytology , Myeloid Cells/immunology , Organ Specificity/drug effects , Organ Specificity/genetics , Organ Specificity/immunology , Plasma Cells/cytology , Plasma Cells/immunology , Plasma Cells/metabolism , Transgenes/immunology
7.
Am J Respir Crit Care Med ; 166(9): 1263-8, 2002 Nov 01.
Article in English | MEDLINE | ID: mdl-12403697

ABSTRACT

Invasive aspergillosis is a common and devastating pneumonia in immunocompromised hosts. Neutrophils are critical for defense against this infection, and ELR+ CXC chemokines are potent neutrophil chemoattractants. We hypothesized that transient lung-specific overexpression of one such ligand, KC, in mice with invasive aspergillosis improves the outcome of disease. We generated mice in which transgenic expression of KC was limited to the lungs and occurred only upon exposure to tetracycline analogues, and we exposed them to doxycycline after the onset of invasive aspergillosis. Transgenic mice had a threefold greater survival, a 74% lower lung fungal burden, a greater magnitude of lung KC induction, and an earlier and higher peak of lung neutrophil influx compared with wild-type mice. In addition to a higher number of neutrophils, we found a 1.8-fold higher number of monocytes-macrophages in the lungs of transgenic mice as compared with wild-type mice. Furthermore, transgenic mice had greater lung expression of interferon-gamma and interleukin-12 in response to infection, suggesting that transgenic expression of KC indirectly regulated the expression of other cytokines associated with improved host defense against this pathogen. Taken together, these data suggest that overexpression of KC in the lung in the setting of established invasive aspergillosis results in improved host defense and outcome of disease.


Subject(s)
Aspergillosis/genetics , Chemokines, CXC , Chemokines/analysis , Chemokines/genetics , Chemotactic Factors/analysis , Chemotactic Factors/genetics , Gene Expression/genetics , Growth Inhibitors/analysis , Growth Inhibitors/genetics , Intercellular Signaling Peptides and Proteins/analysis , Intercellular Signaling Peptides and Proteins/genetics , Outcome Assessment, Health Care , Animals , Aspergillosis/immunology , Aspergillosis/mortality , Aspergillus fumigatus/genetics , Aspergillus fumigatus/immunology , Aspergillus fumigatus/pathogenicity , Chemokine CXCL1 , Chemokines/immunology , Chemotactic Factors/immunology , Disease Models, Animal , Gene Expression/immunology , Growth Inhibitors/immunology , Intercellular Signaling Peptides and Proteins/immunology , Mice , Mice, Transgenic , Severity of Illness Index
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