Interleukin 12, interferon gamma, and tumor necrosis factor alpha are the key cytokines of the generalized Shwartzman reaction.

Abstract

SummaryThe Shwartzman reaction is elicited by two injections of lipopolysaccharide (LPS) in mice. The priming LPS injection is given in the footpad, whereas the lethal LPS challenge is given intravenously 24 h later. The injection of interferon 3, (IFN-'y) or interleukin 12 (IL-12) instead of the LPS priming injection induced the lethal reaction in mice further challenged with LPS. Antibodies against IFN-q/when given together with the priming agent, prevented the lethal reaction in mice primed with either LPS, IL-12, or IFN-3'. Antibodies against IL-12, when given together with the priming agent, prevented the lethal reaction in mice primed with either LPS or IL-12 but not with IFN-% These results strongly suggest that LPS induces the release of IL-12, that IL-12 induces the production of IFN-% and that IFN-7 is the cytokine that primes macrophages and other cell types. Upon LPS challenge, the lethal Shwartzman reaction is induced by a massive production of inflammatory cytokines that act on the target sites already sensitized by IFN-7. If mixtures of TNF and IL-1 or mixtures of TNF and IFN-3' are used to challenge mice previously primed with IFN-7 or ILo12, mortality is induced. In the same conditions, the individual cytokines or a mixture of IL-1 and IFN-3' do not replace the LPS challenge. When the mice are primed with LPS, the combination of TNF, IL-1, and IFN-7 induced only a partial mortality incidence suggesting that the involvement of other LPS-induced factors. Bacterial LPS is a cell wall component of Gram-negative bacteria that is responsible for most of the toxic manifestations associated with bacterial infections. In mice, a lethal shock syndrome, known as the generalized Shwartzman reaction, can be elicited by two consecutive injections of LPS (for review see 1). A priming dose of LPS, injected intradermall), in the footpad (f.p.)l, is followed after 24 h by an intravenous challenge injection of LPS. After this challenge injection, which is not lethal per se, the mice die within the following 48 h from disseminated intravascular coagulation, vascular occlusion, hemorrhage, perivascular accumulation of leukocytes, and necrosis (2). This hypersensitivity reaction occurs only if the time interval between these injections is crucially fixed at between 18 and 24 h. There is no response when the intravenous challenge of LPS is given either earlier or later, or when the order of priming and challenge 1 Abbreviations used in thispaper: f.p., footpad; h, human; m, mouse; MIF, macrophage inhibiting factor; R, receptor. injections is reversed. FinaUy, the reaction does not occur if both the LPS injections are intradermal or if the priming dose of LPS exceeds an optimum. The careful dosage and timing of the LPS injections and the need of specific routes of administration indicate that the Shwartzman reaction is elicited by induced endogenous factors acting in a precise time sequence. IFN-'y, TNF, and IL-1 are known to be involved in the pathogenesis of the generalized Shwartzman reaction. IFN-7 seems important ...

Interleukin 12 Levels During the Initial Phase of Septic Shock With Purpura in Children: Relation to Severity of Disease

“…17 Similar findings were reported in a model of a generalized Shwartzmann reaction in mice. 24 In baboons challenged with Escherichia coli 23 the systemic release of IL-12 p40 and p70 was also reported. Our study confirms that circulating levels of IL-12 are also increased in human sepsis.…”

“…7 The role of IFN-g during in vitro LPS-challenge, 30 in vivo endotoxemia in mice, [16][17][18][19][20] or the generalized Shwartzman reaction in mice, 24,33,34 has been well established. Disseminated intravascular coagulation and shock associated with meningococcal sepsis are considered to be the clinical counterparts of the ''classical'' generalized Shwartzmann reaction.…”

Recurrent miscarriages: What is the role of cytokines?

“…The 'priming agent' may be cortisone itself, through non-specific mechanisms involving monocytes and natural killer (NK) cells [15]. Tumor necrosis factor-a (TNF-a), interferon-g (IFN-g) and interleukin-2 (IL-2) have been identified as key cytokines for the generalized Shwartzman reaction [16]. Thus the maternal immune system is suppressed in one model, but primed to respond in the other.…”

Protective role of NK1.1+ cells in experimentalStaphylococcus aureusarthritis

“…B9 cells were harvested from tissue culture flasks, seeded into microtitre plates (Nunc, Roskilde, Denmark) at the concentration of 5000 cells per well, and cultured in Iscove's medium supplemented with 5 × 10 ¹5 M 2-mercaptoethanol (2-ME), 5% fetal calf serum (FCS; Seralab, Sussex, UK), penicillin 100 U/ml, and streptomycin 100 mg/ml, and serum samples were added. 3 H-thymidine was added after 68 h of culturing, and the cells were harvested 4 h later. The samples were tested in two-fold dilutions and compared with a recombinant mouse IL-6 standard (Genzyme, Cambridge, MA).…”

“…In both cases, the contribution of NK cells to the disease process is dependent on the swift production of interferon-gamma (IFN-g), before antigenspecific responses have come into effect [1,3]. In vitro studies have shown that upon stimulation of human lymphocytes with Staphylococcus aureus antigens, primarily NK cells become activated and produce IFN-g [4,5].…”