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Eur J Immunol. Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Eur J Immunol. 2016 May ; 46(5): 1067–1081. doi:10.1002/eji.201545828.
Suppression of Innate Inflammation and Immunity by Interleukin Family Member Interleukin-37 Charles A. Dinarello1,2, Claudia Nold-Petry3, Marcel Nold3, Mayumi Fujita1, Suzhao Li1, Soohyun Kim1,4, and Philip Bufler5
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1University
of Colorado Denver, Aurora, CO, USA 2Radboud University Medical Center, Nijmegen, The Netherlands 3Monash University, Melbourne, Australia 4Konkuk University, Seoul, Republic of Korea 5Ludwig-Maximilian-University, Munich, Germany
Abstract
Author Manuscript
IL-37 is unique in the IL-1 family in that unlike other members of the family, IL-37 broadly suppresses innate immunity. IL-37 can be elevated in humans with inflammatory and autoimmune diseases where it likely functions to limit inflammation. Transgenic mice expressing human IL-37 (IL37-tg) exhibit less severe inflammation in models of endotoxin shock, colitis, myocardial infarction, lung and spinal cord injury. IL37-tg mice have reduced antigen-specific responses and dendritic cells (DCs) from these mice exhibit characteristics of tolerogenic DCs. Compared to aging wild-type (WT) mice, aging IL37-tg mice are protected against B-cell leukemogenesis and heart failure. Treatment of WT mice with recombinant human IL-37 has been shown to be protective in several models of inflammation and injury. IL-37 binds to the IL-18 receptor but then recruits the orphan IL-1R8 (formerly TIR8 or Sin order function as an inhibitor. Here we review the discovery of IL-37, its production, release and mechanisms by which IL-37 reduces inflammation and suppresses immune responses. The data reviewed here suggest a therapeutic potential for IL-37.
Keywords Autoinflammation; Caspase-1; IL-1 Family; Toll Receptors
Introduction Author Manuscript
Human IL-37 is a member of the IL-1 gene family. In 2010, ten years after its discovery in 2000 by in silico research, there were only 10 publications about this cytokine, but during the past 5 years and as of this writing, the number has increased to 110. A growing number of recent milestone reports reveal that IL-37 plays a pivotal role in limiting innate inflammation as well as suppressing acquired immunity. Importantly, reducing endogenous IL-37 in human cells reveals that IL-37 limits the production of cytokines induced by IL-1 and Toll-like Receptors (TLR) [1] as well as urate crystals [2]. However, unlike all members
Correspondence to C.A.D. [email protected]. Conflict of interest. The authors declare no financial or commercial conflict of interest.
Dinarello et al.
Page 2
Author Manuscript
of the family, there is no IL-37 in the mouse; therefore, establishing a role for this cytokine in IL-37 deficient mice is not possible. Nevertheless, transgenic mice expressing the human IL-37 gene (IL-37-transgenic, IL37-tg) have revealed the broad anti-inflammatory properties of this cytokine. IL37-tg mice exhibit a remarkable protection from endotoxemia, colitis and spinal cord contusion injury to metabolic syndrome and myocardial ischemia [1, 3-8]. Similarly, recombinant IL-37 treatment in wild-type (WT) mice also affords protection in models of endotoxemia, metabolic syndrome, acute lung injury, spinal cord injury, myocardial infarction, asthma and ischemic liver disease [8-13].
Author Manuscript
Table 1 lists the spectrum of changes in innate inflammation mediated by IL-37 either in vitro or in vivo in IL37tg mice. The phenotype of the IL37-tg mice also extends to indirectly limit acquired immunity (Table 2). For example, IL37-tg mice exhibit a marked reduction to antigen specific challenge [14]. With recombinant IL-37 being highly effective in suppressing innate inflammation in WT mice and with studies on IL-37 levels in human diseases, the data support the development of IL-37 as a biologic for treating human inflammatory and autoimmune diseases. This review provides the first comprehensive summary of this neglected but unique cytokine and how IL-37 limits innate inflammation and suppresses immune responses.
In silico discovery of IL-37
Author Manuscript
As reviewed in [15], the identification of IL-37 was reported by three independent groups in the year 2000 [16-18]. There are 5 transcripts for the human IL37 gene (IL-37a-e) but the role of each, such as specific activity and abundance, remains unknown. As shown in Figure 1, IL-37 isoforms a, b and d share exons 4, 5 and 6; the extracellular activity of recombinant IL-37 is located in these exons whereas exons 1, 2 and 3 may be cleaved extracellularly by unknown proteases. The gene for IL-37 is found within the IL-1 gene cluster on chromosome 2q12-13 and lies in close proximity to the regulatory regions for IL-1α and IL-1β [19]. Upon LPS stimulation in human blood monocytes and macrophages, IL-1α, IL-1β and IL-37 are simultaneously transcribed [19].
Author Manuscript
There is no mouse gene coding for IL-37. There is also no IL-37 gene in chimpanzees, our closest genetic relative, although IL-37 is present in the gorilla and other primates [20]. It is not possible to know whether there was an ancient IL-37 in the mouse or chimpanzee that was lost through evolution. The first exon of IL-37 is present in the mouse but there is no open reading frame. One explanation is that an insertion by endogenous retroviruses disrupted an ancient IL-37 in the mouse as well as in the chimpanzee. Our search for the other IL-37 exons has failed (also Idan Cohen, personal communication). During human evolution, mutations in the IL-37 protein occurred such that there are common 14 variants in the populations; however, 3 variants account for 97% of variants [21]. There are two major haplotypes: Haplotype 1 consists of the IL37 reference gene plus Variant 1 and Haplotype 2 consists of Variant 2. Haplotype 2 is present in 16% of Africans and 7% in the world [21]. Variant 1 has two amino acids differences with Reference IL37: G31V and T42A. Variant 2 has 5 amino acid difference with Reference IL37: P50R, Asn50S, P108L, Y164R and D218N. IL-37 gene expression is elevated in psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis [22-27]. A single nucleotide polymorphism (SNP) in IL37b (rs381107)
Eur J Immunol. Author manuscript; available in PMC 2017 May 01.
Dinarello et al.
Page 3
Author Manuscript
results in a mutation at amino acid 42 (T to A), which is associated with disease activity in autoimmune diseases.
Production, Processing and Release of IL-37 Production
Author Manuscript
Using immunohistochemistry, the IL-37 protein has been shown to be expressed by human blood monocytes, tissue macrophages, synovial cells, tonsillar B cells, plasma cells, neoplastic cells as well as epithelial cells of the skin, kidney and intestine. IL-37 is not constitutively expressed by blood monocytes from healthy subjects but rather induced by IL-1β, TLR agonists or TGF-β [1]; in human keratinocytes, beta-defensin-3 induces IL-37 [28]. In the human lung type II epithelial cell, lipoarabinomannan from Mycobacterium tuberculosis induces IL-37 production via up regulating ERK1/2 and p38 [29]. The abundance of IL-37 transcripts is low in human blood monocytes and dendritic cells due to an instability sequence in IL37. This instability sequence limits mRNA half-life of IL-37 [30]. Indeed, despite having a CMV promoter, resting mRNA levels for IL-37 in IL37-tg mice is either absent or low but rapidly increases with inflammation [1, 3, 8, 14]. Even in stimulated human blood monocytes, the level of IL-37 protein is low at 10-20 pg/million cells. Despite low production, recombinant IL-37 is highly active. As listed in Table 1, studies have employed picomolar concentrations of recombinant IL-37 to reduce LPSinduced IL-1β, IL-6 and TNF production in vitro. As shown in Table 3, the administration of 1 microgram or less of IL-37 to WT mice reduces circulating levels of IL-1β, TNF-α and IL-6 [9], neutrophil infiltration into the lungs [10], myocardial monocyte infiltration following infarction [11] and airway hype-responsiveness following antigen challenge [13].
Author Manuscript
Processing and release
Author Manuscript
Similar to other members of the IL-1 family, the IL-37 precursor contains no classical signal peptide. The precursor can be observed by western blotting of endotoxin-stimulated human blood monocytes [31]. Concentrations of IL-37 in the circulation of healthy humans are low (
Eur J Immunol. Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Eur J Immunol. 2016 May ; 46(5): 1067–1081. doi:10.1002/eji.201545828.
Suppression of Innate Inflammation and Immunity by Interleukin Family Member Interleukin-37 Charles A. Dinarello1,2, Claudia Nold-Petry3, Marcel Nold3, Mayumi Fujita1, Suzhao Li1, Soohyun Kim1,4, and Philip Bufler5
Author Manuscript
1University
of Colorado Denver, Aurora, CO, USA 2Radboud University Medical Center, Nijmegen, The Netherlands 3Monash University, Melbourne, Australia 4Konkuk University, Seoul, Republic of Korea 5Ludwig-Maximilian-University, Munich, Germany
Abstract
Author Manuscript
IL-37 is unique in the IL-1 family in that unlike other members of the family, IL-37 broadly suppresses innate immunity. IL-37 can be elevated in humans with inflammatory and autoimmune diseases where it likely functions to limit inflammation. Transgenic mice expressing human IL-37 (IL37-tg) exhibit less severe inflammation in models of endotoxin shock, colitis, myocardial infarction, lung and spinal cord injury. IL37-tg mice have reduced antigen-specific responses and dendritic cells (DCs) from these mice exhibit characteristics of tolerogenic DCs. Compared to aging wild-type (WT) mice, aging IL37-tg mice are protected against B-cell leukemogenesis and heart failure. Treatment of WT mice with recombinant human IL-37 has been shown to be protective in several models of inflammation and injury. IL-37 binds to the IL-18 receptor but then recruits the orphan IL-1R8 (formerly TIR8 or Sin order function as an inhibitor. Here we review the discovery of IL-37, its production, release and mechanisms by which IL-37 reduces inflammation and suppresses immune responses. The data reviewed here suggest a therapeutic potential for IL-37.
Keywords Autoinflammation; Caspase-1; IL-1 Family; Toll Receptors
Introduction Author Manuscript
Human IL-37 is a member of the IL-1 gene family. In 2010, ten years after its discovery in 2000 by in silico research, there were only 10 publications about this cytokine, but during the past 5 years and as of this writing, the number has increased to 110. A growing number of recent milestone reports reveal that IL-37 plays a pivotal role in limiting innate inflammation as well as suppressing acquired immunity. Importantly, reducing endogenous IL-37 in human cells reveals that IL-37 limits the production of cytokines induced by IL-1 and Toll-like Receptors (TLR) [1] as well as urate crystals [2]. However, unlike all members
Correspondence to C.A.D. [email protected]. Conflict of interest. The authors declare no financial or commercial conflict of interest.
Dinarello et al.
Page 2
Author Manuscript
of the family, there is no IL-37 in the mouse; therefore, establishing a role for this cytokine in IL-37 deficient mice is not possible. Nevertheless, transgenic mice expressing the human IL-37 gene (IL-37-transgenic, IL37-tg) have revealed the broad anti-inflammatory properties of this cytokine. IL37-tg mice exhibit a remarkable protection from endotoxemia, colitis and spinal cord contusion injury to metabolic syndrome and myocardial ischemia [1, 3-8]. Similarly, recombinant IL-37 treatment in wild-type (WT) mice also affords protection in models of endotoxemia, metabolic syndrome, acute lung injury, spinal cord injury, myocardial infarction, asthma and ischemic liver disease [8-13].
Author Manuscript
Table 1 lists the spectrum of changes in innate inflammation mediated by IL-37 either in vitro or in vivo in IL37tg mice. The phenotype of the IL37-tg mice also extends to indirectly limit acquired immunity (Table 2). For example, IL37-tg mice exhibit a marked reduction to antigen specific challenge [14]. With recombinant IL-37 being highly effective in suppressing innate inflammation in WT mice and with studies on IL-37 levels in human diseases, the data support the development of IL-37 as a biologic for treating human inflammatory and autoimmune diseases. This review provides the first comprehensive summary of this neglected but unique cytokine and how IL-37 limits innate inflammation and suppresses immune responses.
In silico discovery of IL-37
Author Manuscript
As reviewed in [15], the identification of IL-37 was reported by three independent groups in the year 2000 [16-18]. There are 5 transcripts for the human IL37 gene (IL-37a-e) but the role of each, such as specific activity and abundance, remains unknown. As shown in Figure 1, IL-37 isoforms a, b and d share exons 4, 5 and 6; the extracellular activity of recombinant IL-37 is located in these exons whereas exons 1, 2 and 3 may be cleaved extracellularly by unknown proteases. The gene for IL-37 is found within the IL-1 gene cluster on chromosome 2q12-13 and lies in close proximity to the regulatory regions for IL-1α and IL-1β [19]. Upon LPS stimulation in human blood monocytes and macrophages, IL-1α, IL-1β and IL-37 are simultaneously transcribed [19].
Author Manuscript
There is no mouse gene coding for IL-37. There is also no IL-37 gene in chimpanzees, our closest genetic relative, although IL-37 is present in the gorilla and other primates [20]. It is not possible to know whether there was an ancient IL-37 in the mouse or chimpanzee that was lost through evolution. The first exon of IL-37 is present in the mouse but there is no open reading frame. One explanation is that an insertion by endogenous retroviruses disrupted an ancient IL-37 in the mouse as well as in the chimpanzee. Our search for the other IL-37 exons has failed (also Idan Cohen, personal communication). During human evolution, mutations in the IL-37 protein occurred such that there are common 14 variants in the populations; however, 3 variants account for 97% of variants [21]. There are two major haplotypes: Haplotype 1 consists of the IL37 reference gene plus Variant 1 and Haplotype 2 consists of Variant 2. Haplotype 2 is present in 16% of Africans and 7% in the world [21]. Variant 1 has two amino acids differences with Reference IL37: G31V and T42A. Variant 2 has 5 amino acid difference with Reference IL37: P50R, Asn50S, P108L, Y164R and D218N. IL-37 gene expression is elevated in psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis [22-27]. A single nucleotide polymorphism (SNP) in IL37b (rs381107)
Eur J Immunol. Author manuscript; available in PMC 2017 May 01.
Dinarello et al.
Page 3
Author Manuscript
results in a mutation at amino acid 42 (T to A), which is associated with disease activity in autoimmune diseases.
Production, Processing and Release of IL-37 Production
Author Manuscript
Using immunohistochemistry, the IL-37 protein has been shown to be expressed by human blood monocytes, tissue macrophages, synovial cells, tonsillar B cells, plasma cells, neoplastic cells as well as epithelial cells of the skin, kidney and intestine. IL-37 is not constitutively expressed by blood monocytes from healthy subjects but rather induced by IL-1β, TLR agonists or TGF-β [1]; in human keratinocytes, beta-defensin-3 induces IL-37 [28]. In the human lung type II epithelial cell, lipoarabinomannan from Mycobacterium tuberculosis induces IL-37 production via up regulating ERK1/2 and p38 [29]. The abundance of IL-37 transcripts is low in human blood monocytes and dendritic cells due to an instability sequence in IL37. This instability sequence limits mRNA half-life of IL-37 [30]. Indeed, despite having a CMV promoter, resting mRNA levels for IL-37 in IL37-tg mice is either absent or low but rapidly increases with inflammation [1, 3, 8, 14]. Even in stimulated human blood monocytes, the level of IL-37 protein is low at 10-20 pg/million cells. Despite low production, recombinant IL-37 is highly active. As listed in Table 1, studies have employed picomolar concentrations of recombinant IL-37 to reduce LPSinduced IL-1β, IL-6 and TNF production in vitro. As shown in Table 3, the administration of 1 microgram or less of IL-37 to WT mice reduces circulating levels of IL-1β, TNF-α and IL-6 [9], neutrophil infiltration into the lungs [10], myocardial monocyte infiltration following infarction [11] and airway hype-responsiveness following antigen challenge [13].
Author Manuscript
Processing and release
Author Manuscript
Similar to other members of the IL-1 family, the IL-37 precursor contains no classical signal peptide. The precursor can be observed by western blotting of endotoxin-stimulated human blood monocytes [31]. Concentrations of IL-37 in the circulation of healthy humans are low (
