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Biomedical subjects

R M Strieter

Publications and source records attributed to R M Strieter.

At least 37 records · Page 2Linked to original sources
PubMed2001

Human immunodeficiency virus type 1 (HIV-1)-induced GRO-alpha production stimulates HIV-1 replication in macrophages and T lymphocytes.

We examined the early effects of infection by CCR5-using (R5 human immunodeficiency virus [HIV]) and CXCR4-using (X4 HIV) strains of HIV type 1 (HIV-1) on chemokine production by primary human monocyte-derived macrophages (MDM). While R5 HIV, but not X4 HIV, replicated in MDM, we found that the production of the C-X-C chemokine growth-regulated oncogene alpha (GRO-alpha) was markedly stimulated by X4 HIV and, to a much lesser extent, by R5 HIV. HIV-1 gp120 engagement of CXCR4 initiated the stimulation of GRO-alpha production, an effect blocked by antibodies to CXCR4. GRO-alpha then fed back and stimulated HIV-1 replication in both MDM and lymphocytes, and antibodies that neutralize GRO-alpha or CXCR2 (the receptor for GRO-alpha) markedly reduced viral replication in MDM and peripheral blood mononuclear cells. Therefore, activation of MDM by HIV-1 gp120 engagement of CXCR4 initiates an autocrine-paracrine loop that may be important in disease progression after the emergence of X4 HIV.

Chemokine CXCL1↗
PubMed2001

Interleukin-8 stimulates human immunodeficiency virus type 1 replication and is a potential new target for antiretroviral therapy.

Production of the C-X-C chemokines interleukin-8 (IL-8) and growth-regulated oncogene alpha (GRO-alpha) in macrophages is stimulated by exposure to human immunodeficiency virus type 1 (HIV-1). We have demonstrated previously that GRO-alpha then stimulates HIV-1 replication in both T lymphocytes and macrophages. Here we demonstrate that IL-8 also stimulates HIV-1 replication in macrophages and T lymphocytes. We further show that increased levels of IL-8 are present in the lymphoid tissue of patients with AIDS. In addition, we demonstrate that compounds which inhibit the actions of IL-8 and GRO-alpha via their receptors, CXCR1 and CXCR2, also inhibit HIV-1 replication in both T lymphocytes and macrophages, indicating potential therapeutic uses for these compounds in HIV-1 infection and AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2001

IL-12 attenuates bleomycin-induced pulmonary fibrosis.

Interleukin (IL)-12 is a potent inducer of interferon (IFN)-gamma. We postulated that IL-12 would attenuate bleomycin-induced pulmonary fibrosis. To test this hypothesis, we administered IL-12 or murine serum albumin to bleomycin-treated mice by daily intraperitoneal injection until day 12. Mice treated with IL-12 demonstrated decreased hydroxyproline levels compared with control treated mice. Furthermore, administration of IL-12 led to a time-dependent increase in both lung and bronchoalveolar lavage fluid IFN-gamma. The antifibrotic effect of IL-12 could be attenuated with simultaneous administration of neutralizing anti-IFN-gamma antibodies. These findings support the notion that IL-12 attenuates bleomycin-induced pulmonary fibrosis via modulation of IFN-gamma production.

Animals↗
PubMed2001

Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation.

Increased levels of the neutrophil chemokine interleukin (IL)-8 in the lungs of severe trauma patients can predict subsequent development of acute respiratory distress syndrome. Because the lungs of brain-dead organ donors can contain high levels of IL-8, we hypothesized that this may predispose to early graft failure in the recipient after lung transplantation. Twenty-six organ donors prospectively satisfying clinical criteria for lung donation underwent bronchoalveolar lavage and lung biopsy to determine the effect of neutrophil infiltration and IL-8 expression in the donor lung on graft function and survival in 26 respective recipients after lung transplantation. Nine recipients developed severe graft dysfunction, of whom six subsequently died (median survival: 24 d [range: 5 to 39 d]); all others survived beyond 6 mo. The IL-8 signal in the donor lung correlated with the percent neutrophils in bronchoalveolar lavage fluid (BALF) before implantation (42.4 +/- 7.24 [mean +/- SE]%, p = 0.03) and with the degree of impairment in graft oxygenation after implantation (p = 0.01). An increased level of IL-8 in the donor BALF was associated with the development of severe early graft dysfunction (p = 0.027) and with early recipient mortality (p = 0.0034). Use of donor lungs with high IL-8 levels is associated with a poor prognosis after lung transplantation. Attenuating the donor's inflammatory response before organ retrieval may improve early outcome after lung transplantation, and help maximize lung use from the existing donor pool.

Bronchoalveolar Lavage Fluid↗
PubMed2001

Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2(-/-) mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.

Animals↗
PubMed2001

Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome.

A patient with adrenocortical carcinoma presented with fever, leukocytosis, and increased acute phase reactants. The tumor was infiltrated with neutrophils. Immunohistochemical staining of the tumor showed positive signal for epithelial neutrophil-activating protein-78, an angiogenic and chemotactic CXC chemokine. Conditioned medium from tumor-derived cells (RL-251) showed high concentration of IL-8, epithelial neutrophil-activating protein-78, Gro alpha, and Gro gamma, angiogenic CXC chemokines with a potential role in tumorigenesis. An adrenal cancer/severe combined immunodeficiency mouse chimera was developed. Mice grew tumors rapidly, and circulating levels of IL-8 and epithelial neutrophil-activating protein-78 were detected. In contrast, animals transplanted with NCI-H295 cells, a nonchemokine-secreting cell line, grew tumors more slowly and did not have detectable chemokine levels. Similar to the patient, mice with RL-251 tumors developed marked leukocytosis and neutrophilia, and their tumors were infiltrated with neutrophils. Mice were passively immunized with epithelial neutrophil-activating protein-78 antisera. A marked decrease in tumor growth was observed. Potential for chemokine production by other adrenocortical tumors was investigated by RT-PCR in archival material. Six of seven adrenal carcinomas and one of three adenomas had cDNA for IL-8; six of seven carcinomas and the three adenomas had cDNA for epithelial neutrophil-activating protein-78. We concluded that the clinical presentation of this case resulted from increased tumor production of chemotactic chemokines. Through their angiogenic and chemotactic properties these chemokines may play an important role in adrenal tumorigenesis.

17-Hydroxycorticosteroids↗
PubMed2001

The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).

BACKGROUND: The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation. MATERIALS AND METHODS: Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay. RESULTS: In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin. CONCLUSIONS: Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS.

Adolescent↗
PubMed2000

The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity.

We have previously shown that members of the ELR(+) CXC chemokine family, including IL-8; growth-related oncogenes alpha, beta, and gamma; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR(+) CXC chemokines has not been determined. Because all ELR(+) CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR(+) CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR(+) CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR(+) CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR(+) CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR(+) CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2(-/-) mice. We thus conclude that CXCR2 is the receptor responsible for ELR(+) CXC chemokine-mediated angiogenesis.

Administration, Topical↗
PubMed2000

Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation.

Idiopathic pneumonia syndrome (IPS) is a significant complication following bone marrow transplantation (BMT). We have developed a murine model in which severe IPS is induced by pre-BMT conditioning and allogeneic T cells and is characterized by the recruitment of host monocytes and donor T cells into the lung by day 7 post-BMT. Chemokines regulate cellular recruitment and the migration of cells into inflammatory lesions. In this study, we examined the profiles of chemokines produced locally in the lung (parenchyma and bronchoalveolar lavage fluid) and systemically (serum) during the generation of IPS in the peri-BMT period. Protein and messenger RNA (mRNA) levels of CC chemokines (monocyte/lymphocyte attractants), especially monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, RANTES (regulated upon activation normal T-cell expressed and secreted), and C10, were preferentially induced in the lung by day 7 postallogeneic BMT. In addition, there was an increase in mRNA for IP-10 (a monocyte and Th1-cell chemoattractant). The CXC chemokines MIP-2 and KC, known neutrophil attractants, were moderately elevated. For the most part, these increases in chemokines were dependent on the coinfusion of allogeneic T cells with the BM inoculum. Ribonuclease protection assay and in situ hybridization analyses post-BMT showed that the lung was a major producer of MCP-1, a potent inducer of monocyte chemotaxis. Increases in MCP-1 levels in the lung preceded host APC influx whereas MIP-1alpha levels accompanied donor T-cell infiltration. In summary, we have shown that monocyte- and T-cell-attracting chemokines are associated with monocyte and T-cell recruitment during IPS.

Animals↗
PubMed2000

Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes.

We investigated the biological role of CC chemokines in the Th1-mediated pathogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice. Whereas an elevated ratio of macrophage inflammatory protein-1alpha (MIP-1alpha):MIP-1beta in the pancreas correlated with destructive insulitis and progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1alpha:MIP-1beta ratio was observed in nonobese diabetes-resistant (NOR) mice. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intraislet Th2 responses, decreased CCR5 expression in islets and potentiated a high ratio of MIP-1beta and monocyte chemotactic protein-1 (MCP-1): MIP-1alpha in the pancreas. Furthermore, NOD.MIP-1alpha-/- mice exhibited reduced destructive insulitis and were protected from diabetes. Neutralization of MIP-1alpha with specific Abs following transfer of diabetogenic T cells delayed the onset of diabetes in NOD.Scid recipients. These studies illustrate that the temporal expression of certain CC chemokines, particularly MIP-1alpha, and the CCR5 chemokine receptor in the pancreas is associated with the development of insulitis and spontaneous type I diabetes.

Adjuvants, Immunologic↗
PubMed2000

The role of the CC chemokine, RANTES, in acute lung allograft rejection.

Lung transplantation is a therapeutic option for patients with end-stage lung disease. Acute allograft rejection is a major complication of lung transplantation and is characterized by the infiltration of activated mononuclear cells. The specific mechanisms that recruit these leukocytes have not been fully elucidated. The CC chemokine, RANTES, is a potent mononuclear cell chemoattractant. In this study we investigated RANTES involvement during acute lung allograft rejection in humans and in a rat model system. Patients with allograft rejection had a 2.3-fold increase in RANTES in their bronchoalveolar lavages compared with healthy allograft recipients. Rat lung allografts demonstrated a marked time-dependent increase in levels of RANTES compared with syngeneic control lungs. RANTES levels correlated with the temporal recruitment of mononuclear cells and the expression of RANTES receptors CCR1 and CCR5. To determine RANTES involvement in lung allograft rejection, lung allograft recipients were passively immunized with either anti-RANTES or control Abs. In vivo neutralization of RANTES attenuated acute lung allograft rejection and reduced allospecific responsiveness by markedly decreasing mononuclear cell recruitment. These experiments support the idea that RANTES, and the expression of its receptors have an important role in the pathogenesis of acute lung allograft rejection.

Acute Disease↗
PubMed2000

Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses in vivo.

Secondary lymphoid tissue chemokine (SLC, also referred to as Exodus 2 or 6Ckine) is a recently identified high endothelial-derived CC chemokine. The ability of SLC to chemoattract both Th1 lymphocytes and dendritic cells formed the rationale to evaluate this chemokine in cancer immunotherapy. Intratumoral injection of recombinant SLC evidenced potent antitumor responses and led to complete tumor eradication in 40% of treated mice. SLC-mediated antitumor responses were lymphocyte dependent as evidenced by the fact that this therapy did not alter tumor growth in SCID mice. Studies performed in CD4 and CD8 knockout mice also revealed a requirement for both CD4 and CD8 lymphocyte subsets for SLC-mediated tumor regression. In immunocompetent mice, intratumoral SLC injection led to a significant increase in CD4 and CD8 T lymphocytes and dendritic cells, infiltrating both the tumor and the draining lymph nodes. These cell infiltrates were accompanied by the enhanced elaboration of Th1 cytokines and chemokines monokine induced by IFN-gamma and IFN-gamma-inducible protein 10 but a concomitant decrease in immunosuppressive cytokines at the tumor site. In response to irradiated autologous tumor, splenic and lymph node-derived cells from SLC-treated tumor-bearing mice secreted significantly more IFN-gamma, GM-CSF, and IL-12 and reduced levels of IL-10 than did diluent-treated tumor-bearing mice. After stimulation with irradiated autologous tumor, lymph node-derived lymphocytes from SLC-treated tumor-bearing mice demonstrated enhanced cytolytic capacity, suggesting the generation of systemic immune responses. These findings provide a strong rationale for further evaluation of SLC in tumor immunity and its use in cancer immunotherapy.

Animals↗
PubMed2000

IL-8 is an angiogenic factor in human coronary atherectomy tissue.

BACKGROUND: Interleukin-8 (IL-8), a CXC chemokine that induces the migration and proliferation of endothelial cells and smooth muscle cells, is a potent angiogenic factor that may play a role in atherosclerosis. Previously, IL-8 has been reported in atherosclerotic lesions and circulating macrophages from patients with atherosclerosis. Therefore, we sought to determine whether IL-8 plays a role in mediating angiogenic activity in atherosclerosis. METHODS AND RESULTS: Homogenates from 16 patients undergoing directional coronary atherectomy (DCA) and control samples from the internal mammary artery (IMA) of 7 patients undergoing bypass graft surgery were assessed for IL-8 content by specific ELISA, immunohistochemistry, and in situ hybridization for IL-8 mRNA. The contribution of IL-8 to net angiogenic activity was assessed using the rat cornea micropocket assay and cultured cells. IL-8 expression was significantly elevated in DCA samples compared with IMA samples (1.71+/-0.6 versus 0.05+/-0.03 ng/mg of total protein; P<0.01). Positive immunolocalization of IL-8 was found exclusively in DCA tissue sections, and it correlated with the presence of factor VIII-related antigen. In situ reverse transcriptase polymerase chain reaction revealed the expression of IL-8 mRNA in DCA tissue. Corneal neovascular response, defined by ingrowth of capillary sprouts toward the implant, was markedly positive with DCA pellets, but no constitutive vessel ingrowth was seen with IMA specimens. Neutralizing IL-8 attenuated both the in vivo corneal neovascular response and the in vitro proliferation of cultured cells. CONCLUSIONS: The results suggest that, in human coronary atherosclerosis, IL-8 is an important mediator of angiogenesis and may contribute to plaque formation via its angiogenic properties.

Angina Pectoris↗
PubMed2000

Expression and contribution of endogenous IL-13 in an experimental model of sepsis.

IL-13 has been shown to exert potent anti-inflammatory properties. In this study, we elucidated the functional role of endogenous IL-13 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that the level of IL-13 increased in tissues including liver, lung, and kidney, whereas no considerable increase was found in either peritoneal fluid or serum after CLP. Immunohistochemically, IL-13-positive cells were Kupffer cells in liver, alveolar macrophages in lung, and epithelial cells of urinary tubules in kidney. IL-13 blockade with anti-IL-13 Abs significantly decreased the survival rate of mice after CLP from 53% to 14% on day 7 compared with control. To determine the potential mechanisms whereby IL-13 exerted a protective role in this model, the effects of anti-IL-13 Abs on both local and systemic inflammation were investigated. Administration of anti-IL-13 Abs did not alter the leukocyte infiltration and bacterial load in the peritoneum after CLP but dramatically increased the neutrophil influx in tissues after CLP, an effect that was accompanied by significant increases in the serum levels of aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine. Tissue injury caused by IL-13 blockade was associated with increases in mRNA and the protein levels of CXC chemokines macrophage inflammatory protein-2 and KC as well as the CC chemokine macrophage inflammatory protein-1alpha and the proinflammatory cytokine TNF-alpha. Collectively, these results suggest that endogenous IL-13 protected mice from CLP-induced lethality by modulating inflammatory responses via suppression of overzealous production of inflammatory cytokines/chemokines in tissues.

Animals↗
PubMed2000

Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule expression in a rat model of venous thrombosis.

Post-thrombotic inflammation probably contributes to chronic venous insufficiency, and little effective treatment exists. IL-10 is an anti-inflammatory cytokine that previously has been shown to decrease perithrombotic inflammation and thrombosis. We investigated in a rat model whether local expression of viral IL-10 (vIL-10) in a segment of vein that undergoes thrombosis would confer an anti-inflammatory effect and how this effect might be mediated. Rats underwent inferior vena cava isolation, cannulation, and instillation of saline or adenovirus encoding either beta-galactosidase or vIL-10. Two days after transfection, thrombosis was induced, 2 days after this the rats underwent gadolinium (Gd)-enhanced magnetic resonance venography exam, and the vein segments were harvested. Tissue transfection was confirmed by either RT-PCR of vIL-10 or positive 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside (X-Gal) staining. vIL-10 significantly decreased both leukocyte vein wall extravasation and area of Gd enhancement compared with those in controls, suggesting decreased inflammation. Immunohistochemistry demonstrated decreased endothelial border staining of P- and E-selectin, while ELISA of vein tissue homogenates revealed significantly decreased P- and E-selectin and ICAM-1 levels in the vIL-10 group compared with those in controls. Importantly, native cellular IL-10 was not significantly different between the groups. However, neither clot weight nor coagulation indexes, including tissue factor activity, tissue factor Ag, or von Willebrand factor levels, were significantly affected by local vIL-10 expression. These data suggest that local transfection of vIL-10 decreases venous thrombosis-associated inflammation and cell adhesion molecule expression, but does not directly affect local procoagulant activity.

Animals↗
PubMed2000

The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis.

Angiogenesis is an absolute requirement for tumor growth beyond 2 mm3 in size. The balance in expression between opposing angiogenic and angiostatic factors controls the angiogenic process. The CXC chemokines are a group of chemotactic cytokines that possess disparate activity in the regulation of angiogenesis. Non-small cell lung carcinoma (NSCLC) has an imbalance in expression of ELR+ (angiogenic) compared with ELR- (angiostatic) CXC chemokines that favors angiogenesis and progressive tumor growth. We found that the level of the ELR- CXC chemokine MIG (monokine induced by interferon gamma) in human specimens of NSCLC was not significantly different from that found in normal lung tissue. These results suggested that the increased expression of ELR+ CXC chemokines found in these tumor samples is not counterregulated by a concomitant increase in the expression of the angiostatic ELR-CXC chemokine MIG. This would result in an even more profound imbalance in the expression of regulatory factors of angiogenesis that would favor neovascularization. We hypothesized that MIG might be an endogenous inhibitor of NSCLC tumor growth in vivo and that reconstituion of MIG in the tumor microenvironment would result in the inhibition of tumor growth and metastasis. In support of this hypothesis, we demonstrate here that overexpression of the ELR-CXC chemokine MIG, by three different strategies including gene transfer, results in the inhibition of NSCLC tumor growth and metastasis via a decrease in tumor-derived vessel density. These findings support the importance of the ELR- CXC chemokine MIG in inhibiting NSCLC tumor growth by attenuation of tumor-derived angiogenesis. Furthermore, these findings demonstrate the potential of gene therapy as an alternative means to deliver and overexpress a potent angiostatic CXC chemokine.

Adenoviridae↗
PubMed2000

Differential roles of IL-18 in allergic airway disease: induction of eotaxin by resident cell populations exacerbates eosinophil accumulation.

Cytokine regulation during an allergic response can dictate the severity of the inflammation and resulting injury. In the present study, we have examined the systemic and local effects of IL-18, a Th1-associated cytokine, on a cockroach allergen-induced airway response. In initial studies, temporal increases in IL-18 levels were observed within the lungs. When IL-18 was neutralized systemically the allergen-associated eosinophil accumulation was significantly accelerated 5-fold by 8 h postchallenge, suggesting a regulatory role for IL-18. Recombinant IL-18 (200 ng) was instilled into the airway at the time of allergen challenge to examine whether a direct impact on local eosinophil accumulation could be induced. When IL-18 was instilled, a significant increase in peribronchial eosinophil accumulation was observed in allergic mice as well as in nonallergic mice. A possible mechanism was observed in a significant increase in eotaxin, but not other eosinophil chemotactic factors, in bronchoalveolar lavage fluid after IL-18 instillation. The role of eotaxin was confirmed using eotaxin -/- mice, which demonstrated significantly less eosinophil accumulation compared with littermate controls. IL-18 was subsequently shown to induce eotaxin production from bronchial epithelial cells and isolated macrophages in in vitro assays. The clinical relevance of these findings was determined in treated mice and demonstrated that neutralization of IL-18 exacerbated, whereas exogenous IL-18 had no effect on airway hyperreactivity. Altogether, these data demonstrate that IL-18 may have multiple functions during an immune response that differ depending upon the local or systemic effects.

Administration, Intranasal↗