Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses

Watson, R. W. G.; Redmond, H.R; Bouchier‐Hayes, David

doi:10.1002/jlb.56.1.95

Cited by 97 publications

(53 citation statements)

References 110 publications

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“…LPS potently stimulates the production of IL-1, and IL-1 has a large number of biological activities (12,31,36,49). Thus, the activities of LPS are believed to be mostly mediated by IL-1 or by a cytokine network involving IL-1.…”

Section: Discussionmentioning

confidence: 99%

Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Oguri

Motegi

Iwakura

et al. 2002

Clin Vaccine Immunol

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Within a few hours of its injection into mice, lipopolysaccharide (LPS) induces hypoglycemia and the production of various cytokines. We previously found that interleukin-1␣ (IL-1␣), IL-1␤, and tumor necrosis factor alpha (TNF-␣) induce hypoglycemia and that the minimum effective dose of IL-1␣ or IL-1␤ is about 1/1,000 that of TNF-␣. In the present study, we examined the contribution made by IL-1 to the hypoglycemic action of LPS. Nine other cytokines tested were all inactive at inducing hypoglycemia. LPS produced hypoglycemia in mice deficient in either IL-1␣ or IL-1␤ but not in mice deficient in both cytokines (IL-1␣ and -1␤ knockout [IL-1␣/␤ KO] mice). IL-1␣, IL-1␤, and TNF-␣ induced hypoglycemia in IL-1␣/␤ KO mice, as they did in normal control mice. The LPS-induced elevation of serum cortisol was weaker in IL-1␣/␤ KO mice than in control mice, and, in the latter, serum cortisol was markedly raised while blood glucose was declining. IL-1␣ decreased blood glucose both in NOD mice (which have impaired insulin production) and in KK-Ay mice (insulin resistant). These results suggest that (i) cortisol may not be involved in mediating the resistance of IL-1␣/␤ KO mice to the hypoglycemic action of LPS, (ii) as a mediator, IL-1 is a prerequisite for the hypoglycemic action of LPS, (iii) IL-1␣ and IL-1␤ perform mutual compensation, and (iv) IL-1 plays a role as the primary stimulator of the many anabolic reactions required for the elaboration of immune responses against infection.The endotoxin or lipopolysaccharide (LPS) of gram-negative bacteria strongly stimulates a variety of reactions involved in immune responses (3,36,45). It is also well known that LPS induces hypoglycemia in experimental animals as well as in humans (4,19,35). Incidentally, we have shown that various mitogenic substances other than LPS also induce hypoglycemia in mice (13).The mechanisms reported to underlie LPS-induced hypoglycemia include an enhanced systemic consumption of glucose (34), depletion of glycogen from liver and muscle (33,46), and impaired hepatic gluconeogenesis (18,26,33). The hyperthermic response often seen soon after LPS injection and the later hypothermic responses do not correspond well with the blood glucose changes induced by LPS (2, 28). Over the years, a variety of causal factors, such as insulin (55), the insulin-like action of LPS itself (50), glucocorticoids (22, 42), hepatic serotonin (14, 15), and other humoral factors (22), have been proposed as possible contributors to the LPS-induced hypoglycemia.We were the first to identify the hypoglycemic humoral factor produced by macrophages as interleukin-1 (IL-1) (16), and indeed recombinant IL-1 was later shown to induce hypoglycemia (8,15,22,48). Although tumor necrosis factor alpha (TNF-␣) induces hypoglycemia in mice, the minimum effective dose of IL-1␣ or IL-1␤ is about 1/1,000 that of TNF-␣ (15).Both IL-1␣ and IL-1␤ are capable of reducing blood glucose in mice at a dose as low as 0.1 g/kg of body weight (2.5 ng/ mouse) when injected intraperitoneally (15). Inte...

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Section: Discussionmentioning

confidence: 99%

Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Oguri

Motegi

Iwakura

et al. 2002

Clin Vaccine Immunol

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“…Studies with isolated monocytes and alveolar macrophages have demonstrated that endotoxin-induced synthesis and release of inflammatory cytokines including IL-6, IL-8 and TNF-α, from these cells is mediated via the cell membrane-bound CD14 receptor and that CD14 receptor activation may occur either in the absence or presence of specific LPS binding proteins (LBP) in the serum [63,64]. Studies, particularly of LPS-induced TNF-α synthesis, have demonstrated that there is a threefold increase in the transcriptional activity and a 100 fold increase in cellular mRNA content [65].…”

Section: Molecular Mechanisms Underlying Endotoxin-induced Proinflammmentioning

confidence: 99%

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

Khair¹,

Davies²,

Devalia³

1996

Eur Respir J

165

118

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“…This syndrome is secondary to the effects of endotoxin, the LPS-containing portion of the bacterial cell wall. Infusion of LPS mimics the endotoxic shock state (1) and results in the production of multiple inflammatory cytokines, including TNFa (2, 3), IL-1 (4,5), and IFNy (6). The toxicity of LPS appears to be mediated by these cytokines as passive immunization against these mediators resulted in decreased mortality (2,(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.

Berg

Kühn²,

Rajewsky³

et al. 1995

J. Clin. Invest.

500

361

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Previous studies in vivo have shown that IL-10 infusion can prevent lethal endotoxic shock. Mice deficient in the production of IL-10 (IL1OT) were used to investigate the regulatory role of IL-10 in the responses to LPS in three experimental systems. In a model of acute endotoxic shock, it was found that the lethal dose of LPS for IL1OT mice was 20-fold lower than that for wild type (wt) mice suggesting that endogenous IL-10 determines the amount of LPS which can be tolerated without death. The high mortality rate of IL1OT mice challenged with modest doses of LPS was correlated to the uncontrolled production of TNF as treatment with anti-TNF antibody (Ab) resulted in 70% survival. Additional studies suggested that IL-10 mediates protection by controlling the early effectors of endotoxic shock (e.g., TNFa) and that it is incapable of directly antagonizing the production and/or actions of late appearing effector molecules (e.g., nitric oxide). We also found that ILAOT mice were extremely vulnerable to a generalized Shwartzman reaction where prior exposure to a small amount of LPS primes the host for a lethal response to a subsequent sublethal dose. The priming LPS dose for IL1OT mice was 100-fold lower than that required to prime wt mice implying that IL-10 is important for suppressing sensitization. In agreement with this assumption, IL-10 infusion was found to block the sensitization step. Interestingly, IL-10 was not the main effector of endotoxin tolerance as ILAOT mice could be tolerized to LPS. Furthermore, IL-10 infusion could not substitute for the desensitizing dose of LPS. These results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LPS although it is not responsible for LPS-induced tolerance. (J. Clin. Invest. 1995Invest. . 96:2339Invest. -2347

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Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses

Cited by 97 publications

References 110 publications

Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.

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