Haptoglobin inhibits the pro-inflammatory activity of HMGB1 (P4177)
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Abstract HMGB1 is a cytokine mediator in the pathogenesis of inflammatory diseases including sepsis (Yang et al, BBA, 2009). Recently we demonstrated that haptoglobin (Hp), a naturally occurring serum protein, binds to HMGB1 and suppresses HMGB1-stimulated TNF and IL-8 release in cultured macrophages. Hp knockout mice subjected to cecal ligation and puncture (CLP)-induced sepsis had significantly higher serum HMGB1 levels and higher mortality rates compared to wild type animals (75% survival in wild type vs. 34% in Hp knockout mice; P<0.05). Wild type mice subjected to CLP and received injections of Hp were twice as likely to survive (63% survival in Hp-treated vs. 33% in vehicle control; P<0.05), suggesting the therapeutic potential of exogenous Hp in sepsis. Hp is composed of alpha and beta subunits in a polymeric form (Yueh, J. Chromat B Life Sci. 2007). Structure-functional analysis revealed that Hp beta subunit alone is sufficient to recapitulate effects of Hp to neutralize HMGB1 in vitro in macrophages. The survival advantage of Hp in CLP-induced sepsis was also fully reproduced by Hp beta. Surface plasmon resonance analysis showed that Hp beta binds HMGB1 with high affinity (Kd = 29 nM). Thus, our data reveal unexpected roles of Hp as an endogenous antagonist of HMGB1, preventing the harmful HMGB1-induced inflammation in sepsis. The essential domain of Hp maps to the beta subunit, making it a target in the design of therapeutics.Keywords:
HMGB1
Haptoglobin
Pathogenesis
Knockout mouse
Abstract Severe sepsis accounts for over 200,000 deaths in US annually (Angus et al, CCM, 2001). The mechanism involves endogenous molecules that impair organ function. Extracellular hemoglobin is one such factor enhancing tissue damage during sepsis. We designed haptoglobin-coated beads for a perfusion system to remove hemoglobin in an experimental sepsis model. Surprisingly, we observed that in addition to removing hemoglobin, haptoglobin beads also captured large amounts of HMGB1. HMGB1 is a major mediator on the final common pathway to lethality in sepsis (Yang et al, BBA 2009). Addition of haptoglobin suppressed HMGB1-stimulated TNF and IL-8 release in cultured macrophages. Haptoglobin knockout mice subjected to cecal perforation-induced sepsis had significantly higher serum HMGB1 levels and higher mortality compared to wild type animals (75% survival in wild type vs. 34% in haptoglobin knockout mice; n=15/group, P<0.05). Treatment with anti-HMGB1 antibodies significantly reduced the mortality in haptoglobin knockout mice (12% survival in control vs. 56% in animals receiving HMGB1 antibodies; n=16/group, P<0.05). Structure-function analysis revealed that haptoglobin beta subunit alone is sufficient to recapitulate the protective effects observed with haptoglobin. These findings indicate that haptoglobin is an endogenous modulator of HMGB1 that is capable of reducing the toxicity of HMGB1 in sepsis. Supported in part by grants from NIH (RO1GM62508, to KJT and RO1GM098446, to HY).
Haptoglobin
HMGB1
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Fever is defined as a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous cytokines, some functioning as pyrogens and others as antipyretics. Previous data obtained with the use of traditional pharmacological techniques, such as the injection of neutralizing antibodies, implicate interleukin (IL)-1 and IL-6 as endogenous pyrogens or inducers of fever. In almost all instances in which the endogenous actions of IL-1 or IL-6 are antagonized, fevers are attenuated. Other cytokines, such as tumor necrosis factor-α (TNF-α) and IL-10, are thought to act as endogenous antipyretics or inhibitors of fever. In several studies, the inhibition of TNF action has enhanced fever. Recently, mice genetically engineered to lack cytokines or their receptors in all tissues of the body have been used to examine the regulation of IL-1, IL-6, TNF, and IL-10 on fever. Data obtained with these mice shed new light on our understanding of cytokine interactions in fever and, in some instances, contradict data obtained with pharmacological methods. This review summarizes the responses of cytokine and cytokine receptor knockout mice to fevers induced by lipopolysaccharide, turpentine, and sepsis.
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Oxidative stress and inflammation are considered an important mechanism for the development of cardiovascular diseases. Cytokines including interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) play an important role in oxidative stress and inflammation. It is known that ambient fine particulate matter ( PM ) exposure is closely associated with cardiovascular diseases and oxidative stress. Caspase-recruitment domain 9 ( Card9 ) signaling is critically involvement in the function of macrophages, neutrophils and monocytes that are important for oxidative stress and inflammation. The present study was designed to evaluate the role of CARD9-mediated signaling in cytokines production in mice with PM exposure. Both male wild-type (WT) C57BL/6 mice (8-10 weeks) and age-matched CARD9 knockout (KO) mice (with C57BL/6 background) were exposed to PM2.5 for 6 weeks via intranasal approach with PBS as the control. Serum concentrations of the cytokines including IL-6, IL-1β, and TNF-α were measured with ELISA in the mice before and after PM exposure. There was no difference in the serum levels of IL-6, IL-1β, or TNF-α between WT mice and CARD9 KO mice exposed to PBS. As expected, PM exposure substantially increased the serum levels of IL-6, IL-1β, and TNF-α in the WT mice (by up to 6 times). However, no significant increase in the serum concentrations for IL-6, IL-1β, and TNF-α was observed in CARD9 KO mice exposed to PM. Increased inflammatory infiltrations in the lungs were observed in the WT mice as compared to the CARD9 KO mice with PM exposure. In conclusion, the present study demonstrated that increased cytokines were produced in WT mice, but not in CARD9 KO mice with PM exposure. The data suggested that CARD9 signaling played a critical role in the production of inflammatory cytokines in the mice in response to PM exposure, and might contribute to the development of cardiovascular diseases related to PM exposure.
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Objective To observe the dynamic change of serum inflammatory cytokine in liver transplant patients with early sepsis.Methods 19 liver transplantation patients were divided into sepsis group(HSS group,n=9) and non-sepsis group(HSNS group,n=10) according to whether the patient developed sepsis or not early after operation(within 14 days).The level of serum inflammatory cytokine was detected at 30 min pre-transplantion and on 1 d,3 d,7 d,14 d post-transplantion.Their change and difference were compared between the two groups.Results The mean time for diagnosis of sepsis was 6 days.Compared with those before transplantation,post-transplant tumor necrosis factor(TNF)-α and interleulin(IL)-10 decreased after a slight increase on post-op day 1(P0.05).Then they kept low in HSNS group,while TNF-α increased again on post-op day 7 in HSS group.High mobility group box 1 protein(HMGB1) messenger ribonucleic acid(mRNA) expression in HSNS group was elevated post transplantion and reached to its peak on day 3.Then it began to decrease and came down to the level of that pre-transplantion.HMGB1 mRNA expression in HSS group was elevated significantly post transplantion and maintained at high level.Its expression was significantly higher than that of HSNS group all the time(all in P0.05).Conclusions In liver transplant patients with early sepsis,TNF-αelevated at the same as sepsis occurred.IL-10 increased later than TNF-α,but neither of them increased persistently during sepsis.HMGB1 increases before sepsis ocurred and maintained at high level.Dynamic mornitoring of HMGB1 expression may help to predict the development of early sepsis after liver transplantation.
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Abstract: Regarding the risk of antibiotic therapy during pregnancy, any medication given to the mother should be according to the indications due to the risk of possible side effects. Antibiotics are one of the most important groups of these medications to be considered. Along with direct antibiotic-induced side effects, indirect pathways also affect the fetus through the maternal changes. According to the data, different cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) are involved in both term and preterm parturition. These cytokines could trigger expression of different substances such as prostaglandins (PGs), their receptors, and PGs synthetizing molecules with already proven roles in parturition. Moreover, IL-1, IL-6, and TNF-α knocked-out mice have delayed parturition and lower levels of PGs compared to the wild types. The earlier-mentioned cytokines are able to induce matrix metalloproteinases and are also involved in parturition. Certain antibiotics have been shown capable of inducing inflammation cascade directly. Both in-vivo and in-vitro studies in human have also demonstrated this inflammation as elevated levels of inflammatory cytokines especially IL-1, IL-6, and TNF-α. This increase has been observed both in the presence and the absence of lipopolysaccharide (LPS). Moreover, antibiotics can induce endotoxemia in healthy cases which finally leads to the pro-inflammatory cytokine release. Regarding the role of mentioned pro-inflammatory cytokines in both term and preterm parturition, it seems that non-indicated use of antibiotics during pregnancy may increase the risk of preterm labor. Keywords: preterm labor, antibiotic, inflammation, interleukin-1, interleukin-6, tumor necrosis factor-α
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Thymic stromal lymphopoietin
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It has been demonstrated that lipopolysaccharide (LPS)-induced cytokine response in patients with sepsis differ from the normal host, yet this has not been controlled for the presence of underlying disease. We studied the ability of LPS and killed gram-negative bacteria (GNB) to induce tumor necrosis factor (TNF)-α and interleukin (IL) 10, and of phytohemagglutinin (PHA) to induce interferon (IFN)-γ, in whole blood from patients with sepsis (SP, n = 20), patients with matched underlying disease and without sepsis (control patients, n = 20), and healthy volunteers (HV, n = 20). LPS-induced TNF-α production was lower in SP (median = 638 pg/mL) compared with control patients (4060 pg/mL;P = 0.003), and control patients production was lower compared with HV (5329 pg/mL;P < 0.001). Pseudomonas aeruginosa-induced TNF-α production was lower in SP (1443 pg/mL) than in control patients (7319 pg/mL;P < 0.05), and was not different between control patients and HV (6612 pg/mL;P = 0.6). IFNγ production was lower in SP (948 pg/mL) compared with control patients (5516 pg/mL;P < 0.001), and the control patients production was lower compared with HV (11,282 pg/mL;P < 0.001). IL-10 production was not different among the three groups. Down-regulation of TNF-α production in patients with sepsis, although not restricted to them, was more pronounced with LPS than with GNB. Although the presence of underlying disease may be involved in the regulatory mechanisms of host response, the use of controls with matched underlying diseases provides strong evidence for the septic condition in the down-regulation of inflammatory response in patients with sepsis.
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The involvement of endotoxin in the development of acute pulmonary inflammation and tumor necrosis factor (TNF) release following inhalation of cotton dust was demonstrated using endotoxin-sensitive C3HeB/FeJ and endotoxin-resistant C3H/Hel mice. These mice were exposed for a maximum of 6 h to atmospheres of either 45 mg/m3 cotton dust or 2.4 μg/m3 lipopolysaccharide (LPS) from Enterobacter agglomerans. Inflammation was assessed from bronchoalveolar lavage (BAL) cell morphology and lung histology. Release of TNF into BAL fluid was measured using a bioassay employing WEHI 13VAR cells and neutralization with rabbit anti-mouse TNF antiserum. Neutrophil influx and TNF release were maximal at 6 in C3HeB/FeJ mice following cotton dust exposure and at 3 h following LPS exposure. By 24 h after the beginning of cotton dust exposure, TNF in C3HeB/FeJ BAL was no longer detectable, whereas neutrophils were still elevated above control values. In endotoxin-resistant C3H/Hel mice, no inflammation or TNF release resulted from inhalation of LPS, and minimal inflammation and TNF release were noted at 9 h following exposure to cotton dust for 3 or 9 h. These results suggest a major role for endotoxin in acute inflammation and TNF release induced by cotton dust inhalation, with a minor role for other components in cotton dust. The TNF release coincided with the inflammatory response to cotton dust or LPS inhalation, suggesting, but not proving, an etiologic role of TNF in these inflammatory reactions.
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