Roles of tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, platelet-activating factor, and arachidonic acid metabolites in interleukin-1-induced resistance to infection in neutropenic mice.
Treatment with a single low dose (80 to 800 ng) of interleukin-1 (IL-1) 24 h before a lethal bacterial challenge in granulocytopenic and in normal mice enhances nonspecific resistance. The mechanism behind this protection has only partially been elucidated. Since IL-1 induces production of tumor necrosis factor alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and arachidonic acid metabolites, we investigated the potential role of these substances in IL-1-induced protection. Low doses of murine TNF-alpha but not of human TNF-alpha enhanced survival, suggesting an effect via the type II TNF receptor rather than the type I TNF receptor, which has little species specificity. In line with this TNF-alpha-induced protection from infection, pretreatment with a low dose of a rat anti-murine TNF-alpha monoclonal antibody tended to inhibit IL-1-induced protection, suggesting a role of TNF-alpha as a mediator of IL-1-induced enhanced resistance to infection. Pretreatment with higher doses of anti-TNF-alpha, however, showed a dose-related protective effect per se, which could be further enhanced by a suboptimal dose of IL-1. A combination of optimal doses of anti-TNF-alpha and IL-1 produced an increase in survival similar to that produced by separate pretreatments. This lack of further enhancement of survival by combined optimal pretreatments suggests a similar mechanism of protection, most likely attenuation of deleterious effects of overproduced proinflammatory cytokines like TNF-alpha during lethal infection. Pretreatment with different doses of GM-CSF before a lethal Pseudomonas aeruginosa challenge in neutropenic mice did not enhance survival. Different doses of WEB 2170, a selective PAF receptor antagonist, of MK-886, a selective inhibitor of leukotriene biosynthesis, or of several cyclooxygenase inhibitors did not reduce the protective effect of IL-1 pretreatment. We conclude that IL-1-induced nonspecific resistance is partially mediated by induction of TNF-alpha and not by GM-CSF, PAF, and arachidonic acid metabolites. The mechanism of action of IL-1 seems to be similar to that of anti-TNF-alpha.
Vogels
M T
MT
Department of Medicine, University Hospital, Nijmegen, The Netherlands.
Hermsen
C C
CC
Huys
H L
HL
Eling
W M
WM
van der Meer
J W
JW
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D007074:Immunoglobulin G / Q000276:immunology; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D009503:Neutropenia / Q000276:immunology; D010972:Platelet Activating Factor / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D007074:Immunoglobulin G; D007375:Interleukin-1; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor