title: Local delivery of soluble interleukin-6 receptors to improve the outcome of alpha-toxin producing Staphylococcus aureus infection in mice.
abstract: Staphylococcal alpha-toxin enhances interleukin (IL)-6 secretion in mice infected with Staphylococcus aureus. The role of alpha-toxin-induced IL-6 secretion in host defense has not been sufficiently clarified. In the present study, IL-6 signaling was transiently regulated using soluble IL-6 receptors (sIL-6R) to investigate the role of IL-6 in the early stage of abdominal S. aureus infection. In mice challenged with bacteria producing high alpha-toxin levels, the local delivery of sIL-6R was effective in improving the survival rate, the resolution of neutrophilia and the bacteria clearance. Mice that had received sIL-6R and survived showed high levels of IL-6, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha. In contrast, mice that died in spite of the delivery of sIL-6R showed high levels of interferon (IFN)-gamma and IL-1alpha and low TNF-alpha level. When the effect of soluble gp130, a sIL-6R antagonist, was examined, the number of neutrophils increased significantly and the MCP-1 level decreased significantly, compared to the group that received sIL-6R alone; the number of viable bacteria also tended to increase as a result of the inhibition of IL-6 signaling. The cellular phosphotyrosine level in alpha-toxin-treated macrophages was reduced in cultures supplemented with recombinant IL-6 in vitro. These results suggest that IL-6 enhances bactericidal activity and reduces the number of immune cells that are activated abnormally through the regulation of inflammatory cytokines during the early stage of infection in alpha-toxin producers.
authors.affiliation: Department of Immunology, School of Health Sciences, Kyorin University, 476 Miyashita, Hachioji-shi, Tokyo 192-8508, Japan. onogawa@kyorin-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Onogawa
mesh_terms: D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D007700:Kinetics; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D010586:Phagocytes / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000008:administration & dosage* / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction; D012995:Solubility; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D019947:Receptors, Interleukin-6; D019000:Phosphotyrosine; D010738:Type C Phospholipases