Relationship between Interleukin‐6 Plasma Concentration in Patients with Sepsis, Monocyte Phenotype, Monocyte Phagocytic Properties, and Cytokine Production

Spittler, Andreas; Razenberger, Martina; Küpper, H.; Kaul, Martin; Hackl, Werner O.; Boltz‐Nitulescu, George; Függer, R.; Roth, Erich

doi:10.1086/317499

Cited by 100 publications

(78 citation statements)

References 35 publications

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“…There is a well described correlation between serum IL-6 levels and poor outcome in sepsis (8,(23)(24)(25)(26), and increased IL-6 is an independent predictor of survival in human sepsis (27). In our mouse model, serum IL-6 and IL-1␤ were markedly attenuated by exogenous CO administration.…”

Section: Discussionmentioning

confidence: 52%

“…Elevated plasma concentrations of a variety of cytokines and chemokines such as tumor necrosis factor-␣, IL-1, and IL-6 have been described in septic patients (5,6). IL-6 is one of the most reliably elevated markers in sepsis (7) and one of the few serum markers that has a demonstrable correlation with mortality rates in humans (8). Knowing the anti-inflammatory effects of CO, we hypothesized that CO would protect against lethality in an animal model of sepsis.…”

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confidence: 99%

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Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1

Morse

Pischke

Zhou

et al. 2003

Journal of Biological Chemistry

343

280

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The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1␤ levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1␤ in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.

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Section: Discussionmentioning

confidence: 52%

mentioning

confidence: 99%

Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1

Morse

Pischke

Zhou

et al. 2003

Journal of Biological Chemistry

343

280

View full text Add to dashboard Cite

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“…This cytokine has been shown to suppress TNF-␣ production either directly or indirectly through the stimulation of corticosterone production (45)(46)(47)(48). IL-6 is a cytokine produced by activated macrophages (49), and overproduction of IL-6 has been shown to correlate with poor outcome in patients with severe sepsis and septic shock (37)(38)(39)(40)(41)(42). In the studies we report, serum levels of IL-6 were significantly increased after infection with S. pyogenes in both mouse strains; however, these levels were greater in susceptible C3H/HeN than in resistant BALB/c mice.…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 is a widely recognized major mediator of Gram-positive sepsis (37)(38)(39)(40)(41). In particular, overproduction of IL-6 has been shown to correlate with poor outcome in patients with severe streptococcal sepsis and septic shock (42).…”

Section: Levels Of Tnf-␣ and Il-6 In Susceptible C3h/hen And Resistanmentioning

confidence: 99%

The Role of the MHC on Resistance to Group A Streptococci in Mice

Goldmann¹,

Lengeling

Bose

et al. 2005

The Journal of Immunology

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The severity of infection with Streptococcus pyogenes is strongly influenced by the host’s genetics. This observation extends to the murine model of streptococcal infection, where the background of the mouse strain determines the infection outcome (BALB/c are resistant, whereas C3H/HeN are susceptible). To determine the extent to which the MHC complex (H2) contributed to diseases susceptibility, the response to S. pyogenes of congenic BALB mice from a resistant background (BALB/c), but carrying the H2k region of susceptible C3H/HeN mice (BALB/k), was examined. BALB/k were as susceptible as the H2 donor strain (C3H/HeN). Linkage analysis performed in F2 backcross ([BALB/c × C3H/HeN] × BALB/c) mice confirmed the presence of a susceptibility locus within the H2 region on proximal chromosome 17. The possibility that modulation of T cell responses to streptococcal superantigens (GAS-SAgs) by different H2 haplotypes may influence disease severity was examined. BALB/k exhibited a significantly stronger response at the level of cell proliferation and cytokine production to GAS-SAgs than did BALB/c mice. However, the fact that T cell-deficient SCID-C3H/HeN mice also exhibited a susceptible phenotype suggests a more important contribution of innate effector cells to disease susceptibility. Lower transcriptional levels of certain inflammation-related regulatory genes located on chromosome 17 were detected in macrophages from susceptible than in those from resistant mice in response to infection. These results suggest that susceptibility to S. pyogenes may be associated with an altered transcription of specific genes that may compromise the endogenous regulatory processes controlling the inflammatory cascade and favor the progression to sepsis.

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“…300 mL that is able to adsorb a broad spectrum of cytokines in the 10-70 kDa range, both including pro-and anti-inflammatory cytokines [53][54][55].…”

Section: When To Commence Adjuvant Therapies?mentioning

confidence: 99%

Can procalcitonin levels indicate the need for adjunctive therapies in sepsis?

Becze¹,

Molnár

Fazakas

2015

International Journal of Antimicrobial Agents

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a b s t r a c tAfter decades of extensive experimental and clinical research, septic shock and the related multiple organ dysfunction still remain the leading cause of mortality in intensive care units (ICUs) worldwide. Defining sepsis is a difficult task, but what is even more challenging is differentiating infection-induced from non-infection-induced systemic inflammatory response-related multiple organ dysfunction. As conventional signs of infection are often unreliable in intensive care, biomarkers are used, of which one of the most frequently investigated is procalcitonin. Early stabilisation of vital functions via adequate supportive therapy and antibiotic treatment has resulted in substantial improvements in outcome over the last decades. However, there are certain patients who may need extra help, hence modulation of the immune system and the host's response may also be an important therapeutic approach in these situations. Polyclonal intravenous immunoglobulins have been used in critical care for decades. A relatively new potential approach could be attenuation of the overwhelming cytokine storm by specific cytokine adsorbents. Both interventions have been applied in daily practice on a large scale, with firm pathophysiological rationale but weak evidence supported by clinical trials. The purpose of this review is to give an overview on the pathophysiology of sepsis as well as the role and interpretation of biomarkers and their potential use in assisting adjunctive therapies in sepsis in the future.

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Relationship between Interleukin‐6 Plasma Concentration in Patients with Sepsis, Monocyte Phenotype, Monocyte Phagocytic Properties, and Cytokine Production

Cited by 100 publications

References 35 publications

Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1

Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1

The Role of the MHC on Resistance to Group A Streptococci in Mice

Can procalcitonin levels indicate the need for adjunctive therapies in sepsis?

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