JOURNAL OF INTERFERON & CYTOKINE RESEARCHVolume 00, Number 0, 2011ª Mary Ann Liebert, Inc.
DOI: 10.1089/jir.2011.0062 Interleukin-6 in Sepsis and Capillary Leakage Syndrome Alexander Kru¨ttgen1 and Stefan Rose-John2 Bacterial sepsis is one of the most frequent and dreaded causes of death in intensive care units. According to thecurrent understanding of sepsis, bacterial components activate innate immune responses via pattern-recognitionreceptors that stimulate signaling pathways, thereby leading to activation of NF-kB and the release of cytokines,alarming the organism and coordinating appropriate defense mechanisms. The resulting ‘‘cytokine storm’’ notonly restricts bacterial invasion; it also harms the host by triggering a hemodynamic collapse with a drop inblood pressure, which could lead to death. One of the cytokines released during sepsis is interleukin-6 (IL-6).
Originally described as a B-cell–stimulating factor, this cytokine has since been shown to have multiple addi-tional functions. Interestingly, there is emerging evidence of IL-6 trans-signaling in the pathogenesis of sepsis.
We review recent findings and discuss whether therapeutic interference with IL-6 trans-signaling may bebeneficial in this important clinical scenario.
ulation cascades (disseminated intravascular coagulation).
Sepsis (etymologically derived from the Greek word ‘‘rwi2‘‘ meaning ‘‘decomposition’’) is a leading cause of Eventually, systolic hypotension and diffuse vasoconstriction death in intensive care units. Sepsis is responsible for 9% of lead to a fatal therapy-refractory ischemia of multiple organs deaths per year in the United States and Germany, despite multiple novel therapeutic approaches tested over the past Usually, sepsis originates from serious infections, such as several decades (Stearns-Kurosawa and others, 2011). Be- pneumonia, or by indwelling medical devices, such as in- cause bacteria predate humans, sepsis probably predates travenous lines, that undergo colonization by microorgan- modern humans as well (Baron and others, 2006).
isms (e.g., bacteria), enabling these invasive pathogens to Operational terms used by clinicians to describe different access the blood stream. The spectrum of bacteria isolated stages of sepsis are systemic inflammatory response syn- from blood cultures of patients with sepsis has changed drome (SIRS), sepsis, severe sepsis, and septic shock profoundly over the past decades. Whereas gram-negative (Stearns-Kurosawa and others 2011). Systemic inflammatory bacteria (such as Pseudomonas aeruginosa) were the most fre- response syndrome is caused by increased levels of pro- quently isolated culprits in the 1970s, gram-positive bacteria inflammatory cytokines in the blood and is formally defined (such as Staphylococcus aureus) and fungi (such as Candida by altered body temperature ( > 38°C or < 36°C), increased albicans) are becoming increasingly relevant. The rapid heart rate ( > 90 beats per minute), altered respiratory rate transmission of plasmid-based antibiotic-resistance genes ( > 20 breaths per minute), and a white blood count > 12,000 among bacteria (Kru¨ttgen and others 2011), the existence of cells/mm3 or < 4,000 cells/mm3. Interestingly, SIRS may also virulence genes, and the propensity of certain bacteria to be caused by noninfectious diseases, such as trauma, pul- adhere on indwelling catheter surfaces, forming biofilms, are monary emboli, and myocardial infarction. In contrast, sepsis contributing to the increases in hospital-acquired infections; is defined as SIRS plus infection, whereas severe sepsis in- such infections are of serious concern for clinicians (Seifert volves sepsis with dysfunction of at least one organ. Finally, septic shock is severe sepsis with hypotension (systolic blood One component of the gram-negative membrane is of par- pressure < 90 mm Hg or mean arterial pressure < 65 mm Hg amount significance for the pathogenesis of sepsis: the bacterial after an adequate fluid infusion). Frequent features in septic endotoxin lipopolysaccharide (LPS). Release of LPS into the shock are a high cardiac output and a low systemic vascular circulation triggers a strong systemic pro-inflammatory re- resistance state associated with diminished myocardial sponse reminiscent of septic shock. Most interestingly, it is function. Blood volume is continually lost into the interstitial actually the host response to LPS (not the intrinsic properties of space (due to capillary leakage; see below) and intracellular endotoxin) that induces the potentially lethal consequences.
locations, and blood vessels are clogged by perturbed coag- This overwhelming response—to which the human species 1Department of Medical Microbiology, RWTH Aachen University Medical Faculty, Aachen, Germany.
2Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
might be especially prone—is associated with dramaticallyincreased serum concentrations of pro-inflammatory cyto-kines, commonly known as ‘‘cytokine storm.’’ Although LPSsare intrinsic components of the outer membrane of gram-negative bacteria, lipoteichoic acids and peptidoglycans servea similar role in gram-positive sepsis (Schmidt and others2011).
Both LPS and lipoteichoic acids bind to Toll-like receptors (TLRs), an important family of pathogen-associated molecular-pattern-recognition receptors alerting the innate immune re-sponse system to the presence of dangerous microorganisms.
Whereas TLR4 is the primary LPS receptor, TLR2 is regarded asthe receptor for lipoteichoic acids (Beutler and Rietschel 2003).
Other TLRs recognize an extensive array of other microbialcomponents from fungi, viruses, and parasites. If pathogensmay escape the extracellular detection by TLRs and manage toinvade into the cytoplasm of their human host cells, theirpresence may still be detected by nucleotide binding oligo-merization domain-like receptors and intracellular TLRs(Stearns-Kurosawa and others 2011).
TLRs trigger intracellular pathways involving the signal- ing molecules MyD88 or TRIF and leading to the activationof the transcription factors NF-kB and c-Jun N-terminal ki-nase, thereby initiating the transcription of pro-inflammatorycytokine genes (Stearns-Kurosawa and others 2011). One ofthe major NF-kB target genes is the cytokine interleukin-6(IL-6). Intriguingly, the plasma concentration of this keycytokine may rapidly increase dramatically. Plasma levels ofIL-6 normally range between 1 and 5 pg/mL and have been Interleukin-6 (IL-6)/soluble IL-6R (sIL-6) trans- reported to reach levels > 1 mg/mL during sepsis (Waage signaling and its inhibition by sgp130Fc. Blood-borne IL-6 and others 1989). Therefore, IL-6 is frequently used as a and sIL-6R form a complex that binds to and activates gly- biomarker for sepsis in intensive care units, especially in the coprotein (gp) 130 at the plasma membrane of target cells (trans-signaling), whereas classic signaling describes bindingof IL-6 to cells co-expressing gp80 and gp130. Recombinant soluble sgp130—consisting of the extracellular domain ofgp130 fused with the Fc part of an antibody—acts as a potent Interleukin-6 is a member of the 4-helical cytokine family, scavenger by competing with surface membrane gp130 for which signals via an 80-kDa cytokine receptor (IL-6R, gly- the binding of the naturally occurring IL-6/sIL-6R complex.
Whereas the monoclonal antibody tocilizumab inhibits both coprotein [gp] 80). Once IL-6 binds to IL-6R, the complex of classic signaling and trans-signaling, sgp130Fc selectively IL-6 and IL-6R associates with the signaling receptor subunit gp130, which thereupon dimerizes and induces intracellularsignaling via the Jak/STAT pathway as well as via the Ras/Map-kinase pathway (Grotzinger and others 1999). Im- others 1997). The sgp130Fc protein has been used as a mo- portantly, only few cells in the body—hepatocytes and some lecular tool to define which gp130-driven murine disease leukocytes—express IL-6R, whereas gp130 is expressed models are driven by classic and trans-signaling (Rose-John ubiquitously (Rose-John and others 2006). Because IL-6 has and others 2007). It turned out that the pro-inflammatory no measurable affinity to gp130, it follows that cells, which activities of IL-6 are mainly driven by IL-6 trans-signaling via do express gp130 but not IL-6R, are not responsive to IL-6 the sIL-6R, whereas anti-inflammatory or regenerative (Scheller and others 2011). However, IL-6 signals by 2 functions rely on classic IL-6 signaling via the membrane- mechanisms: (1) via the ubiquitous transmembrane gp130: bound receptor (Scheller and others 2011). Of note, it has ‘‘classic’’ signaling using membrane-bound IL-6R (gp80) and been shown that dying neutrophils, which are the first line of F1 c (2) via trans-signaling using soluble IL-6R (sIL-6R) (Fig. 1).
defense of the body during infectious diseases, release the Therefore, cells expressing only gp130 and not IL-6R are sIL-6R and thereby lead to an attraction of mononuclear responsive to IL-6 in complex with the sIL-6R (Chalaris and cells, which are needed for the resolution of the inflamma- tory process (Chalaris and others 2007).
Even more interestingly, trans-signaling is selectively in- hibited by soluble gp130. Guided by seminal initial structure- function analysis of IL-6 (Brakenhoff and others 1989;Kru¨ttgen and others 1990), designer cytokines such as the Pro-inflammatory cytokines play a pivotal role in the agonist Hyper-IL6 (consisting of IL-6 fused by a linker to sIL- pathogenesis of sepsis. Tumor necrosis factor-a (TNF-a) and 6R) and the inhibitor sgp130Fc have been genetically en- IL-1b are probably the best-examined pro-inflammatory cy- gineered, adding to our repertoire of tools to elucidate or tokines. In animal studies, the sole injection of high concen- manipulate IL-6 signaling in vitro and in vivo (Grotzinger and trations of TNF-a or IL-1b has lethal consequences (Stearns- Kurosawa and others 2011). Unexpectedly, the blood levels of these key cytokines turned out to be of limited use asclinical markers for at-risk patients. Even more disappoint- Blood vessels are lined with endothelial cells that are in- ingly, numerous clinical studies failed to demonstrate robust volved in the regulation of blood pressure. Cell adhesion clinical benefits from pharmacologic inhibition of TNF-a and molecules, such as vascular-endothelial (VE) cadherin, form IL-1b (Stearns-Kurosawa and others 2011). As discussed cell–cell adherens junctions by connecting neighboring en- below, this might have been caused by the complexity of dothelial cell membranes. Clinically, sepsis is associated with sepsis with—perhaps simultaneously—hyper-inflammatory tissue edema caused by vascular leakage through endothelial and anti-inflammatory processes, seriously complicating the cells (endothelial leakage) that impairs oxygenation of tissues clear-cut stratification of patients and thereby hampering the (Lee and Slutsky 2010). Signal transduction pathways trig- decision about which patients profit at which time point gered by inflammatory mediators lead to phosphorylation and endocytosis of VE-cadherin in endothelial cells, giving Besides IL-1b and TNF-a, a few other interleukins are also rise to gaps in the endothelial barrier and resulting in serious of paramount importance. Among these, IL-6 is firmly es- loss in barrier function. An important recent paper demon- tablished as a clinically suitable biomarker for sepsis. In strated the decisiveness of capillary leakage for mortality in seminal studies, Waage and coworkers (1989) observed high murine sepsis: London and Li (2011) showed that sealing levels of IL-6 and its association with fatal sepsis in patients vascular leaks by infusion of recombinant slit (a soluble with meningococcal infection. Since then, many other studies protein best known for its effects in axon guidance of nerve confirmed and extended these results. For instance, evalua- cells) completely protected mice from death induced by tion of postoperative patients with severe sepsis showed that multiple infectious agents. In line with this, the late Judah in survivors, IL-6 significantly decreased during the first 2 Folkman demonstrated that therapeutic application of tet- weeks; in nonsurvivors, IL-6 mostly increased within the racycline might fulfill a similar role (Fainaru and others second week (Frink and others 2009; Tschaikowsky and others 2011). Although IL-6 is an established prognostic Is there a link between IL-6 and vascular leakage during marker for mortality in sepsis because of its higher diag- sepsis? In a visionary paper published in 1997, Ciliberto and nostic discriminative ability, procalcitonin has overtaken IL-6 coworkers showed that vascular endothelial cells express in terms of clinical significance (Stearns-Kurosawa and gp130 but not IL-6R and respond to trans-signaling by IL6/ sIL-6R (Romano and others 1997). In sepsis, considerable The increased levels of the key cytokine IL-6 correlating amounts of both IL-6 and sIL-6R are present in the blood with mortality raised the intriguing hypothesis that IL-6 (Frieling and others 1995), which is separated from organ signaling plays a mechanistic role in human sepsis. Indeed, tissues by gp130-expressing vascular endothelial cells. IL-6 is many studies in mice and cell cultures have corroborated produced in high amounts upon bacterial infection (Waage this idea. Remick and coworkers established that measuring and others 1989), whereas sIL-6R protein is generated by IL-6 concentrations 6 hours after injury infliction is an ac- neutrophils, which are likely to be the first cells to encounter curate predictor of mortality from experimental sepsis in a invading bacteria (Chalaris and others 2007). Therefore, mouse model (Remick and others 2002). However, initial blood-borne IL-6/sIL-6R complexes are bound to interact work with IL-6 knock-out mice was rather disappointing with gp130-expressing endothelial cells lining blood vessels.
because it turned out that IL-6 per se might not be of lethal What are the likely signaling consequences? importance: These mice had no altered mortality in sepsis A recent paper from the field of cancer biology provided (Remick and others 2005). Later on, however, IL-6 signaling us with a possible answer. Lo and others (2011) showed that via the gp130 receptor was found to be of paramount im- IL-6/sIL-6R signaling on human umbilical vascular endo- portance because mice lacking this receptor in the liver were thelial cells triggered phosphorylation and redistribution of protected against an infection with the common sepsis VE-cadherin, leading to vascular leakage. Because human pathogen Streptococcus pyogenes (Klein and others 2007). In umbilical vascular endothelial cells are a standard model for line with these results, gp130 (F/F) knock-in mice expressing the study of endothelial cells in sepsis, one effect of IL-6 a gp130 receptor variant with an overactive STAT3 response trans-signaling in sepsis might be a capillary leakage syn- were hypersensitive to LPS-induced sepsis (Greenhill and Fig. 2). This term describes the breakdown of the others 2011). Moreover, it was shown that trans-signaling in vascular-endothelial barrier function that normally regulates vascular endothelial cells seems to play a major role in sepsis the delicate distribution of nutritional compounds, fluids, because IL-6 trans-signaling in these cells modulated TLR4- and leukocytes between blood and tissues. Increased endo- dependent inflammatory responses (Greenhill and others thelial permeability by disruption of VE-cadherins function results in trans-endothelial flow of fluid and interstitial During shock, the refractory drop in blood pressure is a edema. This dramatically impairs tissue oxygenation due to dire clinical problem. Interestingly, a link between IL-6 sig- increased viscosity of the blood and increased tissue pres- naling and blood pressure was established; peripheral va- sure, contributing to therapy-refractory shock (Stearns- sodilatation in human patients is most strongly associated with increased IL-6 levels in blood (Hartemink and Groe- Besides the unexpected role of IL-6 in triggering vascular neveld 2011). In addition, another interesting study found leakage in vascular endothelial cell, another recent study that serum IL-6 correlated with endothelial dysfunction provided an equally important rationale for interfering with (Esteve and others 2007). Therefore, an emerging question IL-6 trans-signaling in sepsis to increase survival outcome was the mechanism by which IL-6 signaling decreased blood (Barkhausen and others 2011). Intestinal epithelial cells pro- pressure and endothelial function, and whether there was a vide a primary physical barrier against bacteria, and the in- relation to the development of septic shock.
tegrity of this barrier is damaged when pathologic events interleukin-6 (IL-6)/soluble IL-6R (sIL-6R) trans-signaling on vascular endo-thelial Normally, adherens junctions betweenneighboring endothelial cells do notpermit uncontrolled influx of fluid fromthe blood into tissues. During sepsis,IL-6/sIL-6R trans-signaling triggersthe disassembly of these adherensjunctions by inducing the phosphory-lation of VE-cadherin. Influx of bloodinto tissues leads to edema, therebycontributing lead to a drop in blood pressure with ensuing necrosis. This Numerous explanations have been brought forward for is a very serious consequence of shock-induced ischemia: The resulting necrosis of the gut–blood barrier leads to an irre- First, interfering with a complex system is complex sistible invasion of the countless gut-resident commensal bacteria, to which resistance is futile. Interestingly, Bar- Second, lack of appropriate stratification of patients might khausen and others (2011) recently showed in a sepsis model have played a role in disappointing statistical effects; sepsis that blocking IL-6 trans-signaling using sgp130Fc blocked encompasses many different entities that have different intestinal epithelial cell apoptosis in the gut and decreased prognoses and different therapeutic needs at different time mortality. Global blockade of IL-6 by a monoclonal antibody points (Bone 1995). Support for ‘‘personalized sepsis medi- had no beneficial effect. Thus, by keeping enteric epithelial cine’’ is based on the finding that blunting inflammation cells alive, blocking IL-6 trans-signaling protects patients improves survival only of animals at a high risk of dying, with sepsis by keeping the important barrier to enteric bac- whereas low-dose glucocorticoids are effective in patients teria sealed, protecting from a ‘‘second front’’ against those with adrenal malfunction (Remick 2007). The need for a opportunistic pathogens that threaten to invade the hosts’ tailored therapy in sepsis is already indicated by the obser- vation that IL-6 levels are significantly higher in gram-negative bacteremia than in gram-positive bacteremia (Alexandraki and Palacio 2010). Thus, if IL-6 indeed turnsout to be a valid therapeutic target in bacterial sepsis, the Studies guided by a detailed understanding of the structure– microbiological origin of sepsis surely needs to be taken into function relationships of IL-6 with its receptors led to the account, most likely resulting in differential dosing of IL-6 development of potent IL-6 inhibitors, such as monoclonal antagonists according to the Gram state of the invading neutralizing antibodies against IL-6 and its gp80 receptor, as well as a soluble gp130 Fc fusion protein that inhibits IL-6/sIL- Third, too late is too late: As a result of therapeutic in- 6R trans-signaling (Brakenhoff and others 1990; Brakenhoff terference with first-line cytokines during the initial phase of and others 1994; Grotzinger and others 1997). Previous studies pathogenesis, therapy may have no benefit when initiated that applied IL-6 inhibitors in murine disease models of ar- too late (e.g., during the subsequent late phases of the clinical thritis and colitis were encouraging and paved the way to course when patients enter the hospital). Indeed, prospective clinical studies (Rose-John and others 2007). As a result of such studies on patients presenting with sepsis showed that in persistent efforts, tocilizumab, a humanized monoclonal anti- most patients, peak levels of key cytokines were present on body that acts as an IL-6 receptor antagonist, has been ap- the day of admission and decreased on the following days proved for the treatment of rheumatoid arthritis (Mima and (Damas and others 1997). Thus, the best time point for in- terfering with first-line cytokines, such as IL-1b and TNF-a, Although this seems to be good news for clinicians hoping might have been missed. Encouragingly, IL-6 levels remain that IL-6 antagonists will also be approved for the treatment high and stable during the course of sepsis (Damas and of sepsis, caution is warranted. So far, the history of the others 1997). The study by Barkhausen and others (2011) search for drugs to treat sepsis is so discouraging that this demonstrated that a therapeutic application of the sgp130Fc field has even been called the ‘‘pharmaceutical graveyard’’ protein 24 hours after the onset of the sepsis model still (Riedemann and others 2003). Many of these failed endeav- ors were aimed at interfering with cytokines known to exert Fourth, there is a lack of appropriate animal models; mice detrimental effects in sepsis. Why did so many previous are mice, and humans are humans. As a species, humans are expeditions—based on good basic science—eventually fail? known to be particularly susceptible to lethal effects LPS.
In addition, regarding IL-6, what could still hold up the view Thus, identification of mechanisms in animals and pharma- that this time (i.e., with research on modulation of IL-6 trans- ceutical blockade of these pathways might not translate into signaling) might be different and that these studies could clinical efficacy in septic humans (Rittirsch and others 2007).
lead to a panacea for this lethal disease? Most dramatically, the shortcoming of animal models for human sepsis became evident in human volunteers in a not affected by deletion of amino acids 1–28. J Immunol phase I study of an experimental anti-CD28 antibody (Sun- tharalingam and others 2006); although this antibody was Brakenhoff JP, Hart M, De Groot ER, Di Padova F, Aarden LA.
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Received 9 July 2011/Accepted 9 September 2011 AU1: Headings are usually omitted at the beginning of an article. After the introductory paragraphs about definitions of sepsis, can ‘‘Signal Transduction’’ be inserted as a heading? AU2: Please use English transliteration of Greek word rather than symbols.
AU3: Please provide an issue number for each journal reference.
AU4: Is the Barkhausen reference in press? Couldn’t find this one on PubMed.

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