Effect of growth factors on Escherichia coli alpha-hemolysin-induced mediator release from human inflammatory cells: involvement of the signal transduction pathway

Abstract

Previously, we have shown that Escherichia coli alpha-hemolysin represents a potent stimulus for inflammatory mediator release (02release, ,-glucuronidase release, and leukotriene generation) from human polymorphonuclear granulocytes (PMN) as well as for histamine release from a human lymphocyte-monocytebasophil cell suspension (LMB). In contrast, the E. coli alpha-hemolysin leads to a downregulation of cytokine release (interleukin 6 , tumor necrosis factor alpha, and IL-1il) from human LMB. This study was undertaken (i) to analyze the priming efficacy of growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte CSF [G-CSF]) on inflammatory mediator release from human PMN and LMB challenged with hemolysin-producing E. coli bacteria as well as with cell-free E. coli alpha-hemolysin and (ii) to identify major components involved in GM-CSF and G-CSF priming. GM-CSF pretreatment led to an increased chemiluminescence response from human PMN by up to 100%, leukotriene B4 generation was enhanced up to fivefold, and histamine release from human LMB increased from 45% ± 15% to 75% ± 5% (mean ± standard distribution) of the total histamine content. G-CSF priming induced an increase in the chemiluminescence response by up to 50% ± 5% from human PMN and an increase in histamine release from human LMB by 20% ± 5%. The growth factors, GM-CSF and G-CSF, modulated neither 0-glucuronidase release from human PMN nor IL-8 release from human PMN and LMB challenged with the E. coli alpha-hemolysin. GM-CSF and G-CSF pretreatment increased the fluoride (NaF)-induced chemiluminescence response by up to 10-fold; the serine/threonine phosphatase inhibitor okadaic acid inhibited GM-CSFand G-CSF-induced priming. NaF-induced histamine release was enhanced up to 60 and 30% by GM-CSF and G-CSF priming, respectively. GM-CSF and G-CSF pretreatment did not modulate phorbol 12-myristate 13-acetate-induced chemiluminescence response or histamine release. GM-CSF by itself induced an increase in 5-lipoxygenase-specific mRNA expression within 5 min. Our results indicate that (i) GM-CSF and G-CSF interact with inflammatory cells via distinct cellular signalling, (ii) the signal transduction pathway is dependent on the cellular mediator, and (iii) the use of growth factors may be a potent tool to influence the clinical outcome in infectious diseases.

Acylation ofEscherichia coliHemolysin: A Unique Protein Lipidation Mechanism Underlying Toxin Function

“…Investigations into the effect of acylation on the ability of sublytic concentrations of HlyA to stimulate a host cell response have been complicated, perhaps significantly, by the presence of LPS in toxin preparations. At least the major component of HlyA binding to granulocytes appears to be non-receptor mediated, with subsequent triggering of the respiratory burst presumably not through the occupancy of a receptor but through a short-circuiting of the classical signal transduction pathway (103,165). Acylation may therefore enhance protein-protein interactions between HlyA and components of a signal transduction pathway, perhaps by targeting to detergent-resistant domains (Fig.…”

Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: A case report

“…It is crucial to find other safe and effective treatment options to manage G-CSF-induced bone pain. Konig and Konig 11 suggested that G-CSFs play a role in the inflammatory pathway by increasing histamine release. We present the first case report that delineates loratadine use to prophylax against severe pegfilgrastim-induced bone pain.…”