Macrophages rapidly internalize their tumor necrosis factor receptors in response to bacterial lipopolysaccharide

Ding, Aihao; Sánchez, Elizabeth; Srimal, Subita; Nathan, Carl

doi:10.1016/s0021-9258(19)84941-4

Cited by 124 publications

(16 citation statements)

References 53 publications

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“…Peritoneal exudates were elicited in CD1 mice (Charles River Breeding Laboratories, Wilmington, MA) with thioglycolate broth (Difco Laboratories, Detroit, MI) and the cells harvested as described (25) . Monolayers of adherent macrophages were obtained by plating 1 x 106 cells/well in 16-mm-diameter wells in plastic trays (Costar Data Packaging, Cambridge, MA) in a-modified MEM (ceMEM ; KC Biological, Lenexa, KS) with 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

“…These mAbs react with cellular proteins of -55 and 75 kD (20), but their binding to PMN has not been documented . On some cells, the number of TNF-R can be increased by treatment with IFN-.y (21), IL-2 (22), or agents that elevate CAMP (23), or decreased by exposure to IL-1 (24), LPS (25), activators of protein kinase C (23,26,27), inhibitors of protein synthesis (28), and drugs that depolymerize (28) or stabilize (29) microtubules. However, binding of TNF did not change after treatment of PMN with LPS (25), cycloheximide (28), or microtubule-disrupting agents (28), and effects of the other regulators on TNF-R of PMN have not been described.…”

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confidence: 99%

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Shedding of tumor necrosis factor receptors by activated human neutrophils.

Porteu

Nathan

1990

The Journal of Experimental Medicine

419

181

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SummaryThe capacity of human neutrophils (PMN) to bind tumor necrosis factor (TNF) was rapidly lost when the cells were incubated in suspension with agents that can stimulate their migratory and secretory responses . Both physiological (poly)peptides (FMLP, C5a, CSF-GM) and pharmacologic agonists (PMN, calcium ionophore A23187) induced the loss ofTNF receptors (TNF-R) from the cell surface. Half-maximal loss in TNF-R ensued after only ti2 min with 10 -7 M FMLP at 37°C, and required only 10-9 M FMLP during a 30-min exposure . However, there were no such changes even with prolonged exposure of PMN to FMLP at 4°or 16°C. Scatchard analysis revealed loss of TNF-binding sites without change in their affinity (Kd -0.4 nM) as measured at incompletely modulating concentrations of FMLP, C5a, PMA, or A23187. The binding of antiTNF-R mAbs to PMN decreased in parallel, providing independent evidence for the loss of TNF-R from the cell surface. At the same time, soluble TNF-R appeared in the medium of stimulated PMN . This inference was based on the PMN-and FMLP-dependent generation of a nonsedimentable activity that could inhibit the binding of TNF to fresh human PMN or to mouse macrophages, and the ability of mAbs specific for human TNF-R to abolish inhibition by PMN-conditioned medium of binding of TNF to mouse macrophages. Soluble TNF-R activity was associated with a protein of Mr -28,000 by ligand blot analysis of cell-free supernatants of FMLP-treated PMN . Thus, some portion of the FMLP-induced loss of TNF-R from human PMN is due to shedding of TNF-R . Shedding was unaffectedby inhibitors of serine and thiol proteases and could not be induced with phosphatidylinositol-specific phospholipase C. Loss of TNF-R from PMN first stimulated by other agents may decrease their responsiveness to TNF. TNF-R shed by PMN may be one source of the TNF-binding proteins found in body fluids, and may blunt the actions of the cytokine on other cells.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Shedding of tumor necrosis factor receptors by activated human neutrophils.

Porteu

Nathan

1990

The Journal of Experimental Medicine

419

181

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“…This increase corresponded to a significant increase in bacterial survival, as seen in chapter 6 (Fig 6 .2.1), where macrophage bactericidal ability was impaired. While TNF-α levels are high, it is possible that the higher levels of LPS in combination with paclitaxel stimulation caused internalization of TNFR (Ding et al, 1989;Ding et al, 1990b). Thus although TNF-α is produced, it maybe unable to exert bactericidal effects due to lack of cellular receptors and this could have caused the increased CFU seen.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the two MSD are similar, however, ixabepilone LPS mimicry status is unknown. It would be worth investigating this, as having LPS mimicry would cause internalization of TNFR (Ding et al, 1989), but lack of LPS mimicry would mean that any TNF-α produced would be utilized for bacterial killing. We found that mycothiazole treated cells had impaired bacterial killing, while still producing relatively high levels of TNF-α.…”

Section: Discussionmentioning

confidence: 99%

“…While paclitaxel has no structural similarity to LPS, it induces normal murine macrophage responses similar to those generated by LPS, including increased production of TNF-α, NO, and IL-1β (Ding et al, 1990b;Kirikae et al, 1996). Murine macrophages also respond to LPS and paclitaxel by reducing cell surface expression of TNFR and increasing production of TNF-α (Ding et al, 1989;Ding et al, 1990b). The LPS mimetic activities of paclitaxel also include activation of NF-κB, tyrosine phosphorylation of MAPK and induction of LPS-inducible gene expression (Manthey et al, 1992;Ding et al, 1993;Perera et al, 1996;Byrd-Leifer C.A.…”

Section: Shared Actions Of Lps and Paclitaxel On Tnf-α Productionmentioning

confidence: 99%

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The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

Joshi¹

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<p>Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections.</p>

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