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/Interleukin‐8 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 interleukin‐8 (IL‐8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed IL‐8 steady‐state 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 IL‐8 steady‐state mRNA levels as compared with adherent PBMC. Adherent PBMC‐associated IL‐8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic IL‐8 paralleled IL‐8 mRNA expression. Antigenic and bioactive IL‐8 were significantly apparent by 4–8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC IL‐8 gene expression was suppressed by either concomitant treatment with actinomycin‐D or cycloheximide, yet specific neutralizing antibodies directed against either IL‐1β or tumor necrosis factor (TNF)‐α failed to alter adherence‐induced steady‐state IL‐8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of IL‐8, 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 typeâ 1 (mycobacterial) and typeâ 2 (schistosomal) immune responses

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141990/1/jlb0363.pd

C‐C chemokine‐induced eosinophil chemotaxis during allergic airway inflammation

The production of eosinophil‐specific 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)‐mediated allergic responses to examine the role of specific C‐C chemokines [macrophage inflammatory protein‐1α (MIP‐1α), RANTES, and monocyte chemoattractant protein‐1 (MCP‐1)] in eosinophil recruitment. We have previously identified a role for MIP‐1α 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 MIP‐1α 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 48–96 h after allergen (SEA) challenge. Utilizing whole‐lung homogenates from allergen‐challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8‐h lung homogenates and peak activity with samples from 24‐h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen‐challenged mice were preincubated in vitro with antibodies specific for MIP‐1α, RANTES, or MCP‐1, a significant reduction in eosinophil chemotaxis was observed with only MIP‐1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP‐1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573–578; 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 Delayed‐Type Hypersensitivity (Schistosoma mansoni egg) and Foreign‐Body‐Type 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 T‐cell‐mediated hypersensitivity lesions induced by Schistosoma mansoni eggs (SE‐GM) and non‐T‐cell‐mediated foreign‐body‐type lesions (FB‐GM) induced by Sephadex beads were examined. Overall, macrophages from both types of lesions produced mainly lipoxygenase pathway metabolites, leukotrienes, and monohydroxyeicosatetraenoic acids (mono‐HETEs). Early after induction (4 days [4D]), SE‐GM showed an augmented zymosan‐stimulated AA release and metabolism compared to resident peritoneal macrophages. Macrophages from mature lesions (8–32D) showed constitutive synthesis of metabolites and were refractory to zymosan stimulation. Both SE‐GM and FB‐GM showed augmented AA uptake incorporating a large proportion into neutral lipids. A direct comparison of SE‐GM and FB‐GM revealed that the T‐cell‐mediated 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