The growing spectrum of anti-inflammatory interleukins and their potential roles in the development of sepsis.

REVIEW

JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 00, Number 00, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jir.2014.0119

Journal of Interferon & Cytokine Research Downloaded from online.liebertpub.com by Uc Davis Libraries University of California Davis on 01/29/15. For personal use only.

The Growing Spectrum of Anti-Inflammatory Interleukins and Their Potential Roles in the Development of Sepsis Hong-qiang Zhao,1,2,* Wei-min Li,3,* Zhong-qiu Lu,4 Zhi-yong Sheng,2 and Yong-ming Yao 2

Sepsis, recognized as a deadly immunological disorder, is one of the major causes of death in intensive care units globally. Traditionally, sepsis was characterized by an excessive systemic proinflammatory response to invasive microbial pathogens. However, failures of highly sophisticated trials directed toward the uncontrolled inflammatory reaction have led to an appeal by experts for reevaluation of the present approach toward sepsis. With accumulated evidence, a principal role for immunosuppression in severe sepsis has been evaluated. Different pathways of negative regulation in the pathophysiological process of sepsis have been investigated. Significant among these regulatory elements are the anti-inflammatory cytokines. In the past few years, several interleukins (ILs) have been identified and characterized, among which IL-35 and IL-37 represent newly identified ones in the spectrum of anti-inflammatory cytokines. In this study, we focus on regulatory cytokines of the IL family (including the old members: IL-4, IL-10, and IL-13, and newly discovered ones: IL-35 and IL37) to address current knowledge regarding their structural and functional characteristics as well as their roles in the development of sepsis. Although the exact roles for these cytokines are pending further elucidation, the current advances in our understanding of mechanisms that regulate the immune responses during severe sepsis may lead to the identification of new diagnostic or treatment targets.

sepsis was considered as 1 of the 5 conditions where hospitalization expenses were the most expensive (Chalupka and Talmor 2012).

Introduction

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epsis, an intricate clinical syndrome arising from the interaction between microbes and host, can end in severe sepsis and septic shock (Levy and others 2003). Sepsis, severe sepsis, and septic shock are major healthcare problems affecting millions of people around the world each year, accounting for one-fourth of deaths, and are increasing in incidence (Dellinger and others 2013). Septic shock had been reported in an epidemiological study as the most common cause of death in noncoronary intensive care units and the 10th leading cause of death in high-income countries (Angus and others 2001). As the growing population at risk for the development of septic complications comprises the increase in the number of elderly and immunocompromised patients, there is a steady rise in the incidence of severe sepsis (Martin and others 2003). Although there is progress in the area of supportive care and immunomodulatory therapies, the mortality rate of severe sepsis remains high (Brun-Buisson 2000). Apart from a clinical challenge, sepsis was also believed to be a large economic burden for global healthcare systems. It was reported that in the United States

Pathophysiology of Septic Response In recent decades, a great number of scientific articles have been published aiming to elucidate the intricate and dynamic pathophysiological mechanisms that cause the heterogeneous sepsis syndrome. It has been shown that the imbalance between proinflammatory and anti-inflammatory responses caused by amplified and subsequently dysregulated host reaction to a microbe infection leads to the development of sepsis (Cohen 2002). Initial host immune response started when invading microorganisms were detected by an innate immune system through pathogen recognition receptors (PRRs), which are expressed on immune cells such as dendritic cells and macrophages as well as epithelial barriers (Akira and others 2006). PRRs recognize the pathogen-associated molecular patterns (PAMPs), which means the macromolecular motives from microorganisms usually comprise lipopolysaccharide (LPS; the main virulence

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Medical School of Chinese People’s Liberation Army, the Chinese PLA General Hospital, Beijing, People’s Republic of China. Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People’s Republic of China. 3 Department of Hepatobiliary Surgery, the 309th Hospital of Chinese PLA, Beijing, People’s Republic of China. 4 Emergency Department, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, People’s Republic of China. *These authors contributed equally to this study. 2

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factor of gram-negative bacteria), lipoteichoic acid (a cell wall component of gram-positive bacteria), bacterial DNA, flagellin, and peptidoglycan (van der Poll and Opal 2008). The interaction between PRRs and PAMPs gives rise to downstream signaling cascades, which ultimately cause the activation of a transcriptional response program. The activation of nuclear factor kB represents one of such responses, which results in the secretion of cytokines, chemokines, and nitric oxide (Akira and Takeda 2004; O’Neill 2011). Generally speaking, sepsis was characterized by an excessive systemic proinflammatory reaction to invasive microbial pathogens. The innate immune response started by interaction between PRRs and PAMPs results in the excessive secretion of cytokines, chemokines, and other inflammatory mediators. A wide variety of inflammatory reactions, including migration of immune cells to the site of infection, which is critical for infection localization, are regulated by cytokines. However, a dysregulated cytokine release may lead to harm the host. One of such typical risks is the endothelial dysfunction with the feature of vasodilation and increased capillary permeability. The frequent symptoms in septic settings, such as hypotension, hemoconcentration, macromolecular extravasation, and edema, are believed to be associated with the leakage syndrome (Rivers and others 2001). Furthermore, accumulated evidence has manifested that various human body physiological courses, including coagulation, metabolism, and neuroendocrine activation, are tightly interlaced with the immune and inflammatory reactions (Atsumi and others 2007; Emonts and others 2007; Levi and van der Poll 2010). Dysregulation of the coagulation system induced by inflammation significantly aggravates the disturbance in coagulation of sepsis, leading to lethal disseminated intravascular coagulation (Hook and Abrams 2012). With the progress of the research, the host immune response in sepsis has been recognized to develop in different, but overlapping, stages. During the course of sepsis, the original excessive systemic proinflammatory response, termed as systemic inflammatory response syndrome (SIRS), overlaps with the counter-regulatory phase, which came to be known as the compensatory anti-inflammatory response syndrome (CARS) (Bone 1996). Functionally, the immune responses during CARS are suggested to work as a brake on systemic inflammation. The entire immune state of 1 patient is dependent on predomination of either SIRS or CARS since they overlap significantly (van der Poll and van Deventer 1999). Immoderate CARS in sepsis is also believed to be harmful to the host. The immunosuppressive state during the periseptic period is mediated by the compensatory secretion of anti-inflammatory mediators and it is believed to be of considerable clinical significance, which is proved by the more virulent infection and higher mortality found in septic patients who get obvious immunoparalysis (Appel and others 1989). Worldwide, researchers have reiterated that studies for sepsis need new directions in research since the failure of a couple of high-profile clinical experiments directed toward SIRS in sepsis (Cohen and others 2012; Wenzel and Edmond 2012). The cause of death for septic patients was highlighted by the postmortem studies, and the immunological defects manifested as impairment of host immunity was highlighted (Boomer and others 2011). Beneficial effects have gained in the treatment of severe sepsis shown by couples of small phase-2 clinical trials of immune-enhancing drugs, thereby substantiating

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the concept that immunosuppression may play an essential role in the development of septic complications (Meisel and others 2009).

Anti-Inflammatory Cytokines in Sepsis Although imperfect, our comprehension on cellular and molecular mechanisms underlying sepsis-caused immunosuppression has largely been expanded during the last 2 decades. Different pathways of negative regulation in the pathophysiological process of sepsis have been investigated (Luan and others 2012). Prominent members among these regulatory components are the anti-inflammatory cytokines. Under pathological conditions, anti-inflammatory cytokines may either provide insufficient control over proinflammatory activities or overcompensate and inhibit the immune response, rendering the host risky to systemic infection (Fig. 1). Multiple factors, including the time of release, the local circumstances where they act, and the existence of competing or synergistic factors, might contribute to the final effect of anti-inflammatory cytokines (Opal and DePalo 2000). In recent years, some newly discovered anti-inflammatory cytokines of interleukin (IL) families such as IL-35 and IL-37 have been studied. In this study, we will discuss the old triad (IL-4, IL-10, and IL-13) and the newcomers (IL-35 and IL-37) of anti-inflammatory cytokines of IL families regarding their basic biological characteristics and potential roles in the development of sepsis (see Table 1 as a summary).

Interleukin-4 IL-4, a multifunctional pleiotropic cytokine with a molecular weight of 15 kDa, is not only produced mainly by activated T cells but also by mast cells, basophils, and eosinophils (Nelms and others 1999). IL-4 shares sequence homology, cell surface receptors, intracellular signaling, and a partial functional effect on cells with IL-13 (LaPorte and others 2008). IL-4 binds to and signals through 2 combinations of 3 receptor subunits: IL-4Ra, IL-13Ra1, and the common gchain (gc). The type I IL-4 receptor (IL-4R), a heterodimer of IL-4Ra and gc, is the main receptor on hematopoietic cells. The type II IL-4R, a heterodimer of IL-4Ra and IL13Ra1 chains, can bind both IL-4 and IL-13 and is thought to be the primary receptor utilized by nonhematopoietic cells (Pillai and Bix 2011). Soluble IL-4 binds with high affinity to the extracellular domain of IL-4Ra and nearly undetectable affinity to either soluble gc or soluble IL13Ra1 (Kraich and others 2006). By contrast, the IL-4/IL4Ra complex binds with detectable though low affinity to soluble gc and IL-13Ra1. Consistent with this, IL-4 signaling complexes are thought to be assembled in a stepwise manner started by the binding of soluble IL-4 to the IL-4Ra subunit, followed by recruitment in the plane of the membrane of either gc or IL-13Ra1 to the IL-4/IL-4Ra complex. Complex assembly initiates intracellular signaling through activation of the Janus kinase ( JAK) 1/3-signal transducer and activator of the transcription (STAT) 6 and IRS1/2phosphatidylinositol 3-kinase (PI3K) pathways. Functionally, IL-4 plays a key role in the regulation of T lymphocyte differentiation. It promotes the differentiation of Th2 cells while inhibiting that of Th1 cells (Seder and others 1992). Being a primary cytokine produced by Th2


ANTI-INFLAMMATORY INTERLEUKINS AND THIER ROLES IN SEPSIS

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FIG. 1. Schematic depiction of immune response directed mainly by cytokines in the development of sepsis, including secretion phase, biological effects, clinical significance, and host outcome. The initial excessive systemic proinflammatory response in sepsis, termed as systemic inflammatory response syndrome (SIRS), overlaps with the counter-regulatory phase referred to as the compensatory anti-inflammatory response syndrome (CARS). SIRS and CARS overlap significantly; hence, the overall immune status of the patient is dependent on which response predominates. TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.

lymphocytes, IL-4 leads to a further enhanced secretion of itself and other anti-inflammatory cytokines, and thus causes the suppression of monocyte-derived proinflammatory cytokines (Opal and DePalo 2000). The role of IL-4 for the pathophysiology of sepsis is profoundly studied. It has been revealed that IL-4 increased survival of mice exposed to lethal doses of LPS (Baumhofer and others 1998). The activation of the STAT6 pathway induced by IL-4 contributes to the suppression of cellmediated immunity and death in animals with severe sepsis (Song and others 2000). However, deleterious effects of IL4 were also described in Staphylococcus aureus-challenged murine septic setting, which indicated a relationship between the effect of IL-4 and the host’s genetic background (Hultgren and others 1999). Human-based studies have shown that the mRNA expression of IL-4 was associated with the survival of patients with severe sepsis; however, no obvious difference of plasma IL-4 levels in septic patients of the day, on admission, were found between survivors and nonsurvivors (Wu and others 2008). Enzyme-linked immunosorbent assays (ELISA) in 56 patients with severe trauma who developed sepsis, of whom 36 died, indicated that IL-4 had no significant correlation with the severity and outcome of sepsis (Surbatovic and others 2007). Recently, an association of IL-4 polymorphism and sepsis has been reported. It was reported that IL-4 promoter polymorphisms might influence the balance between Th1 and Th2 responses, and thus predispose trauma patients to the development of sepsis (Gu and others 2011). Studies up to now have demonstrated that IL-4 plays a critical role in the pathogenesis of septic complication; however, more work needs

to be done to elucidate its precise mechanism during the course of the disease.

Interleukin-10 IL-10 was initially described as a cytokine synthesis inhibitory factor produced by Th2 cells that inhibit the function of Th1 cells (Fiorentino and others 1989). It is now recognized that numerous types of immune cells, such as monocytes, macrophages, B and T lymphocytes, and natural killer cells, can express and secrete this 35-kDa homodimeric cytokine-IL-10 (Latifi and others 2002). Two distinct chains (IL-10R1 and IL-10R2), which are part of the class II cytokine receptor family (CRF2), constitute IL-10R (Sabat and others 2010). In 1993, the murine IL-10R1 was first cloned by Moore and others (Ho and others 1993). The sequence of human IL-10R1, which is 60% identical and 73% similar to the murine chain, was published by the same group 1 year later (Liu and others 1994). IL-10R1 whose encoding gene is located on chromosome 11 has been identified as a glycosylated protein with the molecular weight of 90–110 kDa (Taniyama and others 1995). Subsequently, IL-10R2 is suggested to be the protein previously known as CRF2-4 since 1993 (Kotenko and others 1997), and the gene for IL-10R2 is located on chromosome 21. It has been demonstrated that the ligandreceptor binding for IL-10 is initiated by its combination to IL-10R1 and this interaction alters the cytokine conformation enabling the subsequent association of the IL-10/IL10R1 complex with IL-10R2 (Yoon and others 2006). Immune cells, especially monocytes and macrophages, express most IL-10R1 (Wolk and others 2002). In comparison with

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Activated T cells, Mast cells, basophils, eosinophils

Th2 cells, basophils, mast cells, natural killer cells, fibroblasts, dendritic cells, alveolar macrophages

CD4 + CD25 + regulatory T cells

Peripheral blood mononuclear cells, monocytes, plasma cells, dendritic cells, epithelial cells, carcinoma cells, testis, thymus, and uterus/ no homolog in mouse was found

IL-4

IL-13

IL-35

IL-37

STAT1/STAT4

Not entirely clear/act as transcriptional modulator or act through SMAD3

Not clear/the binging to the IL-18Ra was observed

JAK-STAT6; PI3K, STAT3, MAPK

IL-4Ra, IL-13Ra1

IL-12b2/gp130

JAK1/3-STAT6; IRS1/2-PI3K

JAK1/ TYK2-STAT3

Signal cascade

IL-4Ra, IL-13Ra1, gc

IL-10R (consists of IL-10R1 and IL-10R2)

Receptor

Anti-inflammatory cytokine/ suppress T cell proliferation and effector functions; induce the conversion of iTR35 Anti-inflammatory cytokine/ limiting tissue injury during infections

Inhibitor of proinflammatory cytokine production/ upregulate MHC-II and CD23

Th1 inhibition/Th2 differentiation/enhance other anti-inflammatory cytokines release/suppress monocyte-derived proinflammatory cytokines secretion

Affect functions of monocytes/ block Th17 proliferation/ promote Tregs survival/ suppress proinflammatory mediator production

Main function

IL-37 transgenic mice are protected against LPS challenge

Not clear

Sepsis models: conflicting Human sepsis: not exactly clear—plasma levels seemed to be not associated with outcome of sepsis/IL-4 promoter may have predictive value Sepsis models: protective role in the development of sepsis/regulate organ-specific inflammation during sepsis Human sepsis: controversial

Sepsis models: conflicting Human sepsis: not exactly clear—might have diagnostic value

Involvement in sepsis and sepsis models

Banchereau and others (2012) Fiorentino and others (1991) Gogos and others (2000) Howard and others (1993) Latifi and others (2002) Moore and others (2001) O’Garra and others (2004) Song and others (1999) Baumhofer and others (1998) Gu and others (2011) Hultgren and others (1999) Nelms and others (1999) Opal and DePalo (2000) Pillai and Bix (2001) Seder and others (1992) Surbatovic and others (2007) Burd and others (1995) Cao and others (2012) Collighan and others (2004) Hancock and others (1998) Hoshino and others (1999) Mannon and Reinisch (2012) Matsukawa and others (2000) Minty and others (1993) Minty and others (1997) Punnonen and others (1993) van der Poll and others (1997) Zurawski and de Vries (1994) Collison and others (2007) Collison and others (2010) Collison and others (2012) Niedbala and others (2007) Olson and others (2013) Kumar and others (2002) Nold and others (2003) Nold and others (2010) Nold and others (2011) Pan and others (2001) Sharma and others (2008) Tete and others (2012)

References

gc, g-chain; JAK, Janus kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription; Tregs, regulatory T cells.

Monocytes, macrophages, T cells, B cells, NK cells

Main sources

IL-10

Cytokine

Table 1. Summary of the Main Features of Anti-Inflammatory Interleukins




IL-10R1, IL-10R2 can be widely and abundantly found in most cells and tissues (Wolk and others 2004; Kunz and others 2006). Unlike the specificity for IL-10R1 to IL-10R complex, IL-10R2 simultaneously constitutes other receptor complexes. Engagement of IL-10 to its receptor induces the phosphorylation of JAK1 and TYK2 and STAT3 (Moore and others 2001). Functionally, IL-10 acts on a wide variety of cells, including monocytes, macrophages, dendritic cells, B and T cells, and even regulatory T cells (Tregs) (O’Garra and others 2004). IL-10 affects many important functions of monocytes, macrophages, and dendritic cells from phagocytosis to the production of cytokines, the expression of costimulators, and the processing as well as presentation of antigens. In addition, IL-10 directly acts on proinflammatory Th17 cells by blocking the proliferation. However, for CD4 + Foxp3 + Tregs, IL-10 promotes its survival and contributes to the function (Banchereau and others 2012). In vitro, IL-10 suppresses the production of proinflammatory mediators, including tumor necrosis factor (TNF)-a, interferon (IFN)-g, IL-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF), from immune cells (Fiorentino and others 1991). These results were also confirmed in vivo studies. The effects of IL-10 in animal infection models are conflicting. It was clearly shown in early studies that IL-10 possessed a protective effect in the pathology of the LPSinduced experimental murine model. Administration of the recombinant IL-10 protein protected mice from lethal endotoxemia, even when injection started 30 min after the LPS challenge (Howard and others 1993). Nevertheless, later studies using the cecal ligation and puncture (CLP) model of polymicrobial sepsis did not always show the beneficial effect of IL-10. Indeed, improved survivals were observed in the CLP model when IL-10 was inhibited at 12 h after onset (Song and others 1999). However, the effect turned to be lethal when administration of neutralizing IL-10 antibodies at the time of the CLP model commenced (van der Poll and others 1995). As multiple biological properties of IL-10 have been demonstrated, it is becoming increasingly apparent that IL-10 as a target of treatment is fraught with theoretical and practical concerns. While as Gogos and others (2000) report, IL-10 might have a diagnostic value for septic patients. They found in their study that the constant overproduction of IL-10 appeared to be the master predictor of severity and deadly outcome, although both the inflammatory and anti-inflammatory responses were deeply augmented. This is of great significance as the definition of the immune status of the patient with sepsis before therapeutic manipulations can be helpful in the selection of patients who may benefit from it.

Interleukin-13 IL-13, a 33 amino acid peptide cytokine, possesses the gene location at human chromosome 5q31, which is resided within a cluster of cytokine genes that consist of IL-3, IL-4, IL-5, and GM-CSF (McKenzie and others 1993). As a Th2 family cytokine, IL-13 was originally identified as a product of activated CD4 + T cells (Minty and others 1993). However, in humans, it has also been reported that basophils, mast cells, natural killer cells, fibroblasts, dendritic cells, and alveolar macrophages have a capacity to produce IL-13

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(Burd and others 1995; Hancock and others 1998; Hoshino and others 1999). Two cell surface receptors have been suggested to be bound by IL-13, but just one of them takes the predominant signal events. IL-13Ra1, which binds IL-13 alone with low affinity, forms high affinity type1 IL-13Rs by dimerizing with IL-4Ra. This type 1 IL-13R transduces intracellular signals through phosphorylation of STAT6 through JAK kinases. The other second messenger molecule has also been suggested to be activated in various cell types, including PI3K, STAT3, and mitogen-activated protein kinase (MAPK). The type 2 IL-13R (IL-13Ra2), which has less definite signaling properties, acts chiefly as a monomer. Affinity for IL-13 Ra2 to IL-13 is higher than that of the dimeric type 1 IL-13Ra1/IL-4Ra receptor. The precise role for IL13Ra2 seemed to be as a sink for IL-13, binding the cytokine and preventing it from working with type I receptor, thereby downregulating the transduction of the intracellular signal (decoy receptor) (Mannon and Reinisch 2012). IL-13 is defined as an anti-inflammatory cytokine that has been shown to downregulate the expression of a number of proinflammatory cytokines (Minty and others 1997). It was reported that LPS-induced IL-6 as well as the mRNA of other proinflammatory cytokines, particularly TNF-a, IL1b, and IL-8, were strongly inhibited by IL-13 (Minty and others 1993; Muchamuel and others 1997; Wong and others 1997). Expression of certain surface antigens such as MHC class II antigens and CD23 was upregulated by this antiinflammatory cytokine (Punnonen and others 1993; Zurawski and de Vries 1994). Through inhibiting the effects of IL-10 and IFN-g, IL-13 suppresses indirectly antibodydependent cellular cytotoxicity in monocytes. It also restrains the expression of tissue factor induced by LPS and protects endothelial and monocyte activation (Zurawski and de Vries 1994). It has been demonstrated that in the murine CLP model, CLP-induced systemic inflammatory response could be balanced by a series of regulatory cytokines (Walley and others 1996; Hack and others 1997). Such fine balance prevents the inflammatory response from converting to pathological, and is self-destructive and fatal to the host (Kellum and Decker 1996). Rapidly, after CLP onset, IL-13 was found to be increased in tissues, including the liver, lungs and kidneys, without elevation of IL-13 levels found in either peritoneal fluid or serum (DiPiro 1997). Neutralization of IL-13 was shown to be detrimental to survival in a murine sepsis model, suggesting a protective role of IL-13 during the development of septic peritonitis (Matsukawa and others 2000). In another study, IL-13 was suggested to be required for mouse survival as a result of CLP and could be a powerful stimulus for chemokine C10 expression in peritoneal macrophages (Steinhauser and others 2000). These studies suggest that IL-13 is critically involved in regulating organ-specific inflammation during the pathological process of sepsis. Indeed, a recent study indicated that the intestinal concentration of IL-13 was dramatically increased in rats with sepsis as compared with healthy normal rats (Cao and others 2012). The potential role of IL-13 in human sepsis seems to be controversial. van der Poll and others (1997) carried out a study based on 42 septic patients and 7 healthy volunteers who received endotoxin intravenously. It was revealed that IL-13 was not found in most of the patients and was not


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induced by endotoxin. These results were not in accordance with animal experiments. However, Collihgan and others (2004) investigated 31 patients with severe sepsis or sepsis shock. They observed that serum IL-13 level in the shock group from the day of admission to day 3 was remarkably higher, while it decreased subsequently to the level similar to that in the nonshock group. IL-13 level was found to be significantly correlated with TNF-a concentration in the study. Another study reported that IL-13 levels were lower in patients with sepsis, and low IL-13 levels in the early hours of sepsis were associated with poor prognosis. However, no correlation between IL-13 levels and other cytokines (IL-1b, IL-10, IL-12, TNF-a) was found (Blanco-Quiro´s and others 2005).

Interleukin-35 IL-35 was found to be a heterodimeric cytokine belonging to the IL-12 family, which is a group of cytokines composing 1 of 5 subunits [p19, p28, p35, p40, and Epstein-Barr virus-induced gene 3 (Ebi3)] that aggregate in various combinations to form IL-12, IL-23, IL-27, and IL-35 (Vignali and Kuchroo 2012). Two subunits, the a subunit (p35, which is encoded by Il12a) and the b subunit (Ebi3, which is encoded by Ebi3), constitute IL-35 (Niedbala and others 2007). Recently, the composition and signaling pathways of the IL-35Rs were characterized in mice. The receptor of IL-35 comprises IL-12b2 and gp130, which are also associated with IL-12 and IL-27Rs, respectively (Collison and others 2012). Following binding of IL-35 to its receptors, the signal is transduced through STAT1 and STAT4 to form a unique heterodimer and results in the expression of the target gene, including p35 and Ebi3, thus leading to a feedback loop enhancing IL-35 expression. Different from other members of the IL-12 family, IL-35 can also regulate the signal through a homodimer of its receptor subunit. However, when such binding happens, only one branch of the signal transduction pathway is activated (either STAT1 or STAT4 for gp130:gp130 or IL12b2:IL-12b2 homodimers, respectively). Although there is a diversity of the ligand-binding mode of IL-35 and its receptors, it seems that IL-35 can exert full functions only by binding to the IL-12b2-gp130 heterodimer receptors. Compared with other IL-12 family members, another feature of IL-35 is that rather than being expressed primarily by antigen-presenting cells IL-35 is expressed primarily by Tregs. Although dozens of reports have been published describing the expression of IL-35 in both thymus-derived and peripheral Tregs, the results taken together suggest that IL-35 may be closely associated with the suppressive activity of Tregs in peripheral tissues rather than a constitutive marker of Tregs (Olson and others 2013). The biological effect for IL-35 is incompletely understood and most of the available data are results from in vitro studies and animal models. With accumulated evidence, IL-35 is recognized as a typical anti-inflammatory cytokine, and the predominant mechanism of suppression associated with the activity of IL-35 is its ability to suppress T cell proliferation and effector functions (Collison and others 2007). Such an observation was not only proved by numerous models by several groups of investigators but also by studies using recombinant agent rIL-35 (Collison and others 2010; Wirtz and others 2011; Tirotta and others 2013).

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It has been demonstrated that Tregs, lacking p35 or EBI3, show decreased regulatory capabilities in vitro. These cells are unable to control T cell proliferation and inhibit the development of inflammatory bowel disease. IL-35 alone is sufficient to inhibit T cell proliferation in vitro. These findings suggest that optimal Tregs suppressive function may require the presence of IL-35 (Collison and others 2007, 2009). In addition to the direct inhibitory effect on naive T cells, IL-35 treatment of human or murine CD4 + T cells could induce their conversion to IL-35-producing T cells, known as iTr35 cells (Collison and others 2010; Chaturvedi and others 2011). It has been reported that maximal Tregs suppression requires not only IL-35 expression but also its contact with naive T cells that can subsequently be converted into iTr35 cells, and thus highlights the importance of IL-35 for the function of Tregs. The suppressive activity of IL-35 is not limited to CD4 + Tregs, as a population of CD8 + CTLA-4 + Tregs was noted to suppress the proliferation of autologous T cells in a contact independent and IL-35-dependent manner (Olson and others 2012). IL-35 has even been shown to exert an effect on suppressing Th17 responses. Tregs expressing IL-35 or rIL35 have been shown to reduce Th17 differentiation as well as the function of Th17 cells (Niedbala and others 2007; Kochetkova and others 2010; Liu and others 2012). Given the direct immunosuppressive potential of IL-35, there has been interest in evaluating the role of IL-35 in the development of a variety of diseases. Several diseases have been shown to be associated with increased IL-35 expression, including various inflammatory diseases, coronary artery disease, and cancer. Niedbala and colleagues found in their studies that IL-35 decreased the severity of collageninduced arthritis in animals (Niedbala and others 2007). Such an effect was mediated by the induction of a CD4 + CD39 + regulatory T population and by the release of IL-10 (Kochetkova and others 2010). The disease severity of a chronic colitis model was also attenuated following the injection of IL-35 (Wirtz and others 2011). In an asthma model, intratracheal instillation of IL-35 decreased disease severity by diminishing the Th2 cell counts and the release of IgE and IgG (Huang and others 2011). Moreover, Icos + Tregs-produced IL-35 downregulated airway hypersensitivity in mice by reducing the production of IL-17 (Whitehead and others 2012). However, the role of IL-35 in the pathological process of sepsis has not been highlighted. Further study is warranted to reveal the exact mechanism of IL-35 in the pathogenesis of sepsis.

Interleukin-37 The IL-1 family of ligands is related to acute and chronic inflammation and plays an essential role in the nonspecific innate response to infection. The biological properties of the IL-1 family of ligands are typically proinflammatory; however, IL-37 sharing the structural pattern of the IL-1 family, but particularly that of IL-18, functions as an antiinflammation cytokine. IL-37, formerly termed IL-1F7, stems from hematopoietic cells and is naturally expressed in organs that comprise epithelial cells (Tete and others 2012). The IL-1F7 cytokine is transcribed as 5 different splice variants, namely IL-1F7 a, b, c, d, and e. IL-1F7b is found to be the largest isoform. It has been reported that IL-37 is bound to the IL-18Ra and it



was also observed in IL-37 transgenic mice (Pan and others 2001; Kumar and others 2002; Nold and others 2011). However, IL-37 appears not to exert its biological effect as a classical receptor antagonist for IL-18. It has been reported that high concentrations of IL-37 do not inhibit the expression of IL-18-induced IFN-g, while IL-18-induced IFNg in the presence of low concentrations of the IL-18-binding protein can be modestly reduced by recombinant IL-37 (Bufler and others 2002). Like IL-1 and IL-18, IL-37 is produced as a precursor that must be cleaved by caspase-1 to be activated. Being activated by caspase-1, IL-37 translocates to the nucleus and serves as a transcriptional regulator and, in turn, enhances the production of LPS-stimulated proinflammatory cytokines (Sharma and others 2008). Other studies also pointed out that the mechanism of IL-37 as an anti-inflammatory cytokine appeared to require SMAD3, which was a downstream kinase of transforming growth factor-b (Grimsby and others 2004; Nold and others 2010). In the form of mRNA and protein, IL-37 has been found in multiple organs, tissues and cell types, including peripheral blood mononuclear cells, monocytes, plasma cells, dendritic cells, epithelial cells, carcinoma cells, testis, thymus, and the uterus. IL-37 is the only IL-1 family member that lacks the homolog in the mouse. IL-37, as a potent anti-inflammatory cytokine, plays a significant role in restricting tissue injury during infections by downregulating the duration and intensity of immune as well as inflammatory responses in animal models (Tete and others 2012). A strain of transgenic mice has been generated to reveal the in vivo biological effect of IL-37, as a mouse homolog for human IL-37 has not been identified (Nold and others 2010). Both heterozygous and homozygous IL-37 transgenic mice breed normally and give rise to no obvious phenotype. IL-37 is not constitutively expressed in these mice even in mRNA levels. However, the expression of IL37 increases upon stimulation with IL-1b or LPS after 4– 24 h, and IL-37 precursor can be detected in peripheral blood cells separated from the transgenic mice. IL-37 transgenic mice were better protected against LPS challenge compared with similarly challenged wild-type mice. They displayed markedly less hypothermia, acidosis, hyperkalemia, hepatitis, and dehydration secondary to LPS challenge. In addition, circulating cytokines were significantly reduced as well as cytokines induced in whole blood cultures and in the lung and spleen cell homogenates. The anti-inflammatory activity of IL-37 was also manifested in a marked reduction in the expression of CD86 and MHC II on dendritic cells isolated from the spleen of IL-37 transgenic mice after LPS challenge (Nold and others 2010).

Conclusion A highly complex network of control elements modulates the human immune response, among which the antiinflammatory cytokines are of profound significance. Under physiological conditions, these cytokine inhibitors serve as immunomodulatory roles that attenuate the injury of sustained or excess inflammatory reactions. However, under pathological conditions, including severe sepsis and septic shock, these anti-inflammatory agents may either inhibit the proinflammatory responses that are insufficient or overcompensate, causing the host a state of immunoparalysis (Kasai and others 1997; Opal and DePalo 2000).

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Although great efforts have been made worldwide in the past decades to elucidate the exact relationship between anti-inflammatory cytokines and septic response, it still seemed mysterious to us as illustrated by this review. The significances of most reviewed ILs in the pathological process of sepsis are not exactly clear both in septic models or human sepsis. Moreover, limited information is available to show marked diagnostic value for septic patients, such as IL-10 and IL-13. The findings of the growing number of new antiinflammatory cytokines and the new features of old cytokines will further elucidate the complicated and dynamic pathophysiological mechanisms underlying severe sepsis. Better understanding of the significance of these anti-inflammatory ILs might provide not only some validation on immune status of septic patients but also potential valuable diagnostic or therapeutic strategies.

Acknowledgments This work was supported, in part, by grants from the National Natural Science Foundation (Nos. 81130035, 81372054, 81272090, 81121004) and the National Basic Research Program of China (No. 2012CB518102).

Author Disclosure Statement The authors declare that they have no competing interests.

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Address correspondence to: Dr. Yong-ming Yao Trauma Research Center First Hospital Affiliated to the Chinese PLA General Hospital Fucheng Road 51 Haidian District Beijing 100048 People’s Republic of China E-mail: [email protected] Received 21 June 2014/Accepted 22 September 2014

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