Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.

Abstract

Leukemia inhibitory factor (LIF) has recently been associated with septic shock in humans. In this study we sought to determine, in mice, the role of LIF in septic shock During sublethal endotoxemia, serum LIF levels, as determined by radio-receptor competition assay, peaked at 2 h and were low (3 ng/ml), whereas in lethal Escherichia coli septic shock serum LIF levels rose progressively (>30 ng/ml) in the premorbid phase coincident with the development of tissue injury. Single i.v. injections of high doses (up to 50 ,ug per mouse) of recombinant murine LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 ,ug per mouse per day) for 3-4 days induced a fatal catabolic state without evidence of preceding hemodynamic collapse or shock. Simultaneous or subsequent administration of high doses of LIF had no effect on mortality from sublethal and lethal E. coli septic shock, whereas prior administration conferred significant protection against lethality (P << 0.001 by log-rank test), an effect that was dose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced serum tumor necrosis factor concentrations (P < 0.05), reduction in the number of viable bacteria (P < 0.05), and prevention of sepsis-induced tissue injury. These observations suggest that systemic LIF production is part of the host response to both endotoxin and sepsis-induced tissue injury.We recently reported that serum concentrations of the cytokine leukemia inhibitory factor (LIF; also known as D-factor) were specifically elevated in patients with septic shock (1) and that the levels correlated with disease severity (2). LIF, originally characterized by its ability to induce differentiation in myeloid cells of the murine Ml leukemia cell line, is a pleiotropic cytokine that has several biological similarities to tumor necrosis factor (TNF) and interleukins IL-1 and IL-6 (reviewed in ref.3), which have also been implicated in the pathogenesis of septic shock (4). All are endogenous pyrogens, stimulate acute-phase protein synthesis, and inhibit lipoprotein lipase (LPL) activity (3). Like TNF, IL-1, and IL-6, LIF can be produced in vitro by a variety of cells, including monocytes-macrophages, fibroblasts, endothelial cells, and activated T lymphocytes, and its production can be induced by stimulation with TNF, IL-1, or lipopolysaccharide (LPS) (3). Cellular receptors for LIF (LIF-Rs) exist in low-and highaffinity forms, and molecular clones encoding the low-affinity murine and human LIF-R a chains have been isolated. Conversion of low-affinity to high-affinity LIF-R status and signal transduction are conferred by the X3 subunit, gpl30, and high-affinity LIF-Rs have been identified on all responsive cell types (3). A heat-labile soluble form of the cellular LIF-R a chain (sLIF-R) has been identified at high concentration in mouse serum (5) and was shown to inhibit the binding of LIF to its cellular receptor and block the ability of LIF to ...

Endogenous leukemia inhibitory factor attenuates endotoxin response

“…15 This interpretation would be coherent with our results, which are consistent with the data showing that an injection of LIF prior to LPS protected the mice from endotoxic shock. 11 Furthermore, we were able to attenuate LPS toxicity in LIFÀ/À mice by exogenous LIF.…”

“…dose of LIF is able to protect mice from the lethal effect of LPS 12 and live E. coli. 11 The protection by prior administration of LIF does not necessarily have to be the same mechanism as the observed sensitization in the absence of LIF. It has been suggested that induction of the APP plays a central role in establishing protection.…”

“…4,7 Clinical studies demonstrated that serum concentrations of LIF are elevated in patients with Gram-negative and meningococcal septic shock 8 and that the levels correlated with the severity of disease. 9 In murine endotoxic shock models LIF is induced after intraperitoneal administration of LPS 10, where it can be detected in circulation after 1-3 h. 10,11 LIF given prior to a lethal challenge to LPS 12 or to live Escherichia coli 11 provided nearly complete resistance to these agents. Furthermore, LIF coinjected with LPS into the rat trachea decreased LPS neutrophil recruitment.…”

Leukemia Inhibitory Factor, Interleukin 6, and Other Cytokines Using the GP130 Transducing Receptor: Roles in Inflammation and Injury

“…These data indicate that LIF is one of the principal agents in the lethality associated with septic shock. Surprisingly, LIF injection prior to a challenge with a high dose of LPS protects against the lethal effects of endotoxin [96,97], suggesting that LIF may also exert anti-inflammatory activities. Similarly, intratracheal coinjection of LIF and LPS inhibits the acute inflammatory response that is usually triggered by LPS alone [98].…”

Leukemia inhibitory factor functions as a growth factor in pancreas carcinoma cells: Involvement of regulation of LIF and its receptor expression

“…Further, LIF was increased as a potent pro-inflammatory cytokine in sepsis (7,8), arthritis (9,10), injury (11) and dermatitis (12). Prior administration of high dose LIF protects from lethality in E. coli-induced septic shock (13). LPS induces 10-fold higher TNF-· and IL-6 serum level and reduces IL-10 production in LIF deficient mice (7).…”