106 research outputs found
The Role of Arachidonic Acid Metabolites in Mononuclear Phagocytic Cell Interactions
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65162/1/j.1365-4362.1986.tb04543.x.pd
Chemokine responses in schistosomal antigen-elicited granuloma formation *
Host immune systems have evolved specialized responses to multicellular parasites. This is well represented by the type 2 granulomatous response to Schistosoma mansoni egg antigens, which is an eosinophil-rich inflammatory response mediated by Th2-associated cytokines. Using Ag-bead models of pulmonary granuloma formation in mice, we defined characteristic chemokine (CK) profiles in the granulomatous lungs. Our findings point to a role for C-C chemokine receptor-2 (CCR2) and CCR3 agonists such as monocyte chemotactic proteins (MCPs) 1/CCL2, 3/CCL7 and 5/CCL12 as important participants that are subject to regulation by Th2 cytokines interleukin (IL)-4 and IL-13. CCR4 and CCR8 agonists are also likely contributors. Analysis of CK receptor knockout mice revealed that CCR2 ligands (e.g. MCP-1 and 5) promoted early phase granuloma macrophage accumulation, whereas anti-MCP-3 (CCL7) antibody treatment abrogated eosinophil recruitment. CCR8 knockout mice also demonstrated impaired eosinophil recruitment but this appeared to be related to impaired Th2 cell function. Transcript analysis of CD4 + T cells generated during schistosome granuloma formation failed to show biased CCR8 expression but, having a more limited receptor repertoire, these cells were likely more dependent on CCR8 ligands. Together, these studies indicate an intricate involvement of chemokines in various stages and aspects of schistosomal egg Ag-elicited granuloma formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74858/1/j.1365-3024.2002.00466.x.pd
Arachidonic acid metabolites regulate interleukin-1 production
We have investigated the role of arachidonic acid metabolites in the regulation of interleukin-1 production by murine peritoneal macrophages. Indomethacin a potent inhibitor of prostaglandin synthesis caused a dose-dependent augmentation of lipopolysaccharide induced interleukin production (up to 7-fold at 5 [mu]M). In contrast, lipoxygenase inhibitors, nordihydroguarietic acid and nafazatrom had no effect at doses that did not significantly decrease prostaglandin synthesis. Added to lipopolysaccharide stimulated cultures, PGE2 suppressed interleukin in a dose-dependent manner. Zymosan induced interleukin was also augmented by indomethacin but unlike lipopolysaccharide treated cultures was suppressed by nordihydroguarietic acid. These data suggest that arachidonate metabolites may be potent autoregulators of macrophage interleukin-1 production.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25698/1/0000252.pd
Mononuclear Cell Adherence Induces Neutrophil Chemotactic Factor/Interleukinâ8 Gene Expression
The accumulation of polymorphonuclear cells (PMN) in tissue is an essential element of the inflammatory response that is important in host defense. Adherence to endothelium constitutes the first step in PMN migration from the vascular compartment to the interstitium. We demonstrate that human peripheral blood mononuclear cells (PBMC) adherent to plastic can result in expression of interleukinâ8 (ILâ8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed ILâ8 steadyâstate mRNA levels by 30 min, peaked at 8 h, and then decreased over the next 16 h. In contrast, nonadherent PBMC (cultured in teflon chambers) expressed less than 25% of the maximal ILâ8 steadyâstate mRNA levels as compared with adherent PBMC. Adherent PBMCâassociated ILâ8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic ILâ8 paralleled ILâ8 mRNA expression. Antigenic and bioactive ILâ8 were significantly apparent by 4â8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC ILâ8 gene expression was suppressed by either concomitant treatment with actinomycinâD or cycloheximide, yet specific neutralizing antibodies directed against either ILâ1ÎČ or tumor necrosis factor (TNF)âα failed to alter adherenceâinduced steadyâstate ILâ8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of ILâ8, and may be essential to the development of the inflammatory response through the elicrtation of PMN.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141636/1/jlb0287.pd
Population analysis of CD4+ T cell chemokine receptor transcript expression during in vivo typeĂą 1 (mycobacterial) and typeĂą 2 (schistosomal) immune responses
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141990/1/jlb0363.pd
CâC chemokineâinduced eosinophil chemotaxis during allergic airway inflammation
The production of eosinophilâspecific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA)âmediated allergic responses to examine the role of specific CâC chemokines [macrophage inflammatory proteinâ1α (MIPâ1α), RANTES, and monocyte chemoattractant proteinâ1 (MCPâ1)] in eosinophil recruitment. We have previously identified a role for MIPâ1α in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIPâ1α and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48â96 h after allergen (SEA) challenge. Utilizing wholeâlung homogenates from allergenâchallenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8âh lung homogenates and peak activity with samples from 24âh lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergenâchallenged mice were preincubated in vitro with antibodies specific for MIPâ1α, RANTES, or MCPâ1, a significant reduction in eosinophil chemotaxis was observed with only MIPâ1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIPâ1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573â578; 1996.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141543/1/jlb0573.pd
Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages
We have investigated the effect of tumor necrosis factor on the release of interleukin-1 and PGE2 from murine resident peritoneal macrophages. Tumor necrosis factor causes an increase in the production of interleukin-1 and PGE2 with a maximum induction for both noted at 5.9 x 10-8M. While indomethacin decreased tumor necrosis factor induced PGE2 production, this cyclooxygenase inhibitor augmented tumor necrosis factor induced interleukin-1 production. Our data suggests that tumor necrosis factor may be an important immunopotentiating agent in addition to its previously described cytolytic and metabolic activities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26197/1/0000276.pd
The role of chemokines in Schistosoma mansoni granuloma formation
The eradication of parasitic diseases, such as schistosomiasis, has been the focus of investigations worldwide for many decades. However, attempts to control their continual spread have, at best, been met with limited success. In the face of these results, it is important to attempt to understand and thus to control the pathology of these widespread diseases. In this review, Nicholas Lukacs, Steven Kunkel, Robert Strieter and Stephen Chensue focus on a family of cytokines that play a pertinent role for leukocyte recruitment in chronic inflammation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31918/1/0000871.pd
Regulation of macrophage tumor necrosis factor production by prostaglandin E2
We have studied the role of prostaglandin E2 on the modulation of tumor necrosis factor by immunologically elicited and lipopolysaccharide treated murine macrophages. Indomethacin, a potent inhibitor of prostaglandin E2 production, caused a dose dependent augmentation of lipopolysaccharide induced tumor necrosis factor production (2-3 fold at 10-7 molar). Tumor necrosis factor was released into the extracellular environment and no activity was found to be associated with membrane or cytosolic fractions. Prostaglandin E2 added to the lipopolysaccharide treated cultures suppressed tumor necrosis factor in a dose dependent manner. In these studies, 10-7 molar PGE2 reduced tumor necrosis factor production to basal levels. These data suggest that PGE2 may be a potent autoregulatory factor that dramatically influences tumor necrosis factor production.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26166/1/0000243.pd
Dynamics of Arachidonic Acid Metabolism in Macrophages From DelayedâType Hypersensitivity (Schistosoma mansoni egg) and ForeignâBodyâType Granulomas
The present study examines the kinetics of arachidonic acid (AA) metabolism by murine macrophages isolated from sites of experimentally induced pulmonary granulomatous inflammation. Macrophages of Tâcellâmediated hypersensitivity lesions induced by Schistosoma mansoni eggs (SEâGM) and nonâTâcellâmediated foreignâbodyâtype lesions (FBâGM) induced by Sephadex beads were examined. Overall, macrophages from both types of lesions produced mainly lipoxygenase pathway metabolites, leukotrienes, and monohydroxyeicosatetraenoic acids (monoâHETEs). Early after induction (4 days [4D]), SEâGM showed an augmented zymosanâstimulated AA release and metabolism compared to resident peritoneal macrophages. Macrophages from mature lesions (8â32D) showed constitutive synthesis of metabolites and were refractory to zymosan stimulation. Both SEâGM and FBâGM showed augmented AA uptake incorporating a large proportion into neutral lipids. A direct comparison of SEâGM and FBâGM revealed that the Tâcellâmediated lesion produced lesser amounts of prostaglandins and leukotrienes and showed reduced incorporation of AA into phosphatidylcholine. These data suggest that AA metabolism by granuloma macrophages is sequentially modified during recruitment and activation at sites of chronic inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141165/1/jlb0671.pd
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