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

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long‐term control of infection while also preventing an over‐zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro‐ and anti‐inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host‐directed therapies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146448/1/imr12671.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146448/2/imr12671_am.pd

Regulation of Monokine Gene Expression: Prostaglandin E2 Suppresses Tumor Necrosis Factor but Not Interleukin‐1α or β‐mRNA and Cell‐Associated Bioactivity

Prostaglandin E2 (PGE2)‐mediated suppression of macrophage interleukin‐1α,β and tumor necrosis factor‐α synthesis was examined at the cellular and molecular levels. Treatment of lipopolysaccharide (LPS)‐stimulated adjuvant‐elicited murine macrophages with 5 × 10‐7M PGE2 caused a 70% reduction in cell‐associated TNF but had no suppressive effect on cell‐associated interleukln‐1 (IL‐1) activity. Consistent with this result, Northern blot and nuclear transcription analyses demonstrated suppression of TNF mRNA but PGE2 had no effect on IL‐1α and IL‐1β mRNA accumulation, as compared to LPS controls. Immunoperoxidase staining for cell‐associated TNFα, IL‐1α, and IL‐1β demonstrated that PGE2 suppressed TNF, but not IL‐1α or ‐β expression, supporting the bioassay data. These results imply that PGE2‐mediated regulation of IL‐1α,β and TNFα is quite distinct. Synthesis of TNF appears to be regulated at least at the level of transcription, whereas that for IL‐1α and ‐β is regulated post‐transcriptionally.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141223/1/jlb0416.pd

Cross-regulatory role of interferon-gamma (IFN-Γ), IL-4 and IL-10 in schistosome egg granuloma formation: in vivo regulation of Th activity and inflammation

This study examined the relationship ofIL-4, IL-10 and IFN-Γ with regard to the local granuloma (GR) and draining lymph node (LN) response to Schistosoma mansoni eggs. Synchronized GR were induced in naive and schistosome-infected mice at the vigorous (8 weeks) and late chronic (20 weeks) stages. In LN cultures, IL-10 and IFN production peaked on day 4 and was greatest for 8 week-infected mice. All GR cultures contained IFN, but compared with naive mice IL-10 production was accelerated at 8 weeks and abrogated at 20 weeks, consistent with expansion and abatement of Th2 activity, Cytokine neutralization was performed in egg-challenged, naive mice that were adoptively sensitized with lymphoid cells from 8 week-infected donors. GR size, GR macrophage tumour necrosis factor (TNF) production and egg antigen-elicited IL-2, IL-4, IL-5, IL-10 and IFN were examined on day 4 of GR formation, Anti-IFN augmented GR area by 40%, increased local IL-4 and IL-10, but decreased IFN and TNF production. In corresponding LN cultures, IFN decreased by about 50%, while IL-2, IL-4, IL-IO and lL-5 increased by nearly two-, four-, five- and six-fold, respectively, Anti-IL-10 did not affect GR size or GR cytokines, but increased IFN levels in LN cultures four-fold and decreased IL-2, IL-4, lL-5 and IL-10. Anti-IL-4 abrogated GR area by 40%, along with a reduction in local IL-4 and TNF production. In LN, IL-4 depletion reduced IL-4 and IL-5 by 60–70% and increased IFN levels. These results support the notion of a cross-regulatory network in which IFN inhibits Th2 and IL-10 inhibits ThI cells. IL-4 fosters Th2 cell differentiation in LN, but also performs a critical recruitment function in the eosinophil-rich schistosome egg-induced GR, whereas IFN contributes to enhanced GR macrophage function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73324/1/j.1365-2249.1994.tb05503.x.pd

TLR9 activation is a key event for the maintenance of a mycobacterial antigen-elicited pulmonary granulomatous response

Type 1 (Th1) granulomas can be studied in mice sensitized with mycobacterium antigens followed by challenge of agarose beads covalently coupled to purified protein derivative. TLR9 is known to play a role in the regulation of Th1 responses; thus, we investigated the role of TLR9 in granuloma formation during challenge with mycobacterium antigens and demonstrated that mice deficient in TLR9 had increased granuloma formation, but a dramatically altered cytokine phenotype. Th1 cytokine levels of IFN-γ and IL-12 in the lungs were decreased in TLR9 –/– mice when compared to wild-type mice. In contrast, Th2 cytokine levels of IL-4, IL-5, and IL-13 were increased in TLR9 –/– mice. The migration of CD4 + T cells in the granuloma was impaired, while the number of F4/80 + macrophages was increased in TLR9 –/– mice. Macrophages in the lungs of the TLR9-deficient animals with developing granulomas expressed significantly lower levels of the classically activated macrophage marker, nitric oxide synthase, but higher levels of the alternatively activated macrophage markers such as ‘found in inflammatory zone-1′ antigen and Arginase-1. These results suggest that TLR9 plays an important role in maintaining the appropriate phenotype in a Th1 granulomatous response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57331/1/2847_ftp.pd

III. Chemokines and other mediators, 8. Chemokines and their receptors in cell-mediated immune responses in the lung

Chemokines constitute a large family of chemotactic cytokines that belong to a super-gene family of 8–10 kDa proteins. The chemokines are considered to be primarily beneficial in host defense against invading pathogens. However, the reactions induced by chemokines can be occasionally excessive, resulting in a harmful response to the host. Recent studies in chemokine biology have elucidated that chemokines are involved in the initiation, development, and maintenance of numbers of diseases including lung diseases. In addition to its chemotactic activity, evidence suggests that chemokines can modify the outcome of the cell-mediated immune responses by altering the Th1/Th2 cytokine profile. Chemokines are also capable of dictating the direction of specific immune responses. Chemokine action is mediated by a large super-family of G-protein coupled receptors, and the receptors are preferentially expressed on Th1/Th2 cells. Certain chemokine receptors are constitutively expressed in immune surveying cells such as dendritic cells and naive T cells. The corresponding chemokines are present in normal lymphoid tissues, suggesting a role of chemokines/receptors in cell homing and cell-cell communication in lymphoid tissue that can be an initial step for immune recognition. Thus, comprehension of the chemokine biology in immune responses appears to be fundamental for understanding the pathogenesis of T cell–mediated immune responses. The following review will highlight the current insight into the role of chemokines and their receptors in the cell-mediated immune response, with a special focus on lung diseases. Microsc. Res. Tech. 53:298–306, 2001. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35184/1/1096_ftp.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

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

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