IL-36γ and Infectious Lung Diseases

Yasuyuki Taooka, Takamasa Hotta, Takeshi Isobe

Yasuyuki Taooka, Department of internal medicine, Akiota hospi¬tal, Hiroshima, Japan
Takamasa Hotta, Takeshi Isobe, Department of internal medicine, division of medical oncology and respiratory medicine, Shimane university faculty of medicine, Izumo, Japan

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Yasuyuki Taooka, MD, PhD, FCCP, FACP, Department of Internal Medicine, Akiota Hospital, Shimodomo-gohchi 236, Akiota-cho, Yamagata-gun, Hiroshima, 731-3622, Japan.
Email: taooka-alg@umin.ac.jp
Telephone: +81-826-22-2299
Fax: +81-826-22-0623

Received: October 16, 2018
Revised: November 1, 2018
Accepted: November 2, 2018
Published online: November 4, 2018


A new comer of Interleukin (IL)-1 family, IL-36γ is known as one of pro-inflammatory cytokines. IL-36γ is produced by keratinocytes, intestinal epithelial cells, bronchial epithelial cells, alveolar macrophages, and lymphocytes, and is realized to be involved in maintenance of innate immunity. Recently, knowledge about IL-36γ and infectious lung diseases have been accumulating. In this draft, we focused on infectious lung diseases and involvement of IL-36γ. Then the future direction of IL-36γ/IL-36 receptor axis immune reaction pathway and therapeutic strategy against acute lung injury was also discussed.

Key words: IL-36γ; IL-1 family; Pneumonia

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Taooka Y, Hotta T, Isobe T. IL-36γ and Infectious Lung Diseases. Journal of Respiratory Research 2018; 4(1): 137-139 Available from: URL: http //www.ghrnet.org/index.php/jrr/article/view/2451


Member of IL-1 family cytokine

In pneumonia, cytokines are generally involved in maintaining pulmonary innate immunity and lung inflammation[1,2]. Although interleukin (IL)-1 family primarily promote inflammation and immune reaction, IL-1 family is also known as both of inflammatory agonist and antagonist. Eleven of IL-1 family member includes IL-1α, IL-1β, IL-1receptor antagonist (RA), IL-18, IL-33, L-36α, IL-36β, IL-36γ, IL-36 RA, IL-37, and IL-38. Among those members, IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ work as inflammatory agonist, and IL-1RA, IL-36RA, IL-37, and IL-38 work as inflammatory antagonist[3]. IL-1 family is divided into 3 groups. They are IL-1 subfamily (IL-1α, IL-1β, IL-33, IL-1RA), IL-18 subfamily (IL-18 and IL-37), and IL-36 subfamily (IL-36α, IL-36β, IL-36γ, IL-38 and IL-36RA). As co-receptors of IL-1 family, 10 members are known as following; IL-1receptor(R)1, IL-1R2, IL-1R accessory protein (IL-1RAcp), IL-18Ra, IL-18b, IL-33R, IL-36R, single Immunoglobulin (Ig) IL-1R-related molecule (SIGIRR), three Ig domain-containing IL-1R related-1 (TIGIRR-1), and TIGIRR-2[3,4].

IL-1 family and Toll-like receptor (TLR) family are known to be shared similar functions[4]. IL-1 family members affect each other, and most of IL-1 family members is associated with innate immunity. In other words, IL-1 family is controlling innate immunity through development, maintenance, and suppression of inflammation.

In this content, we focus on IL-36γ related lung inflammation. And we also discussed about IL-36γ as the biomarker for inflammatory lung disease, and inhibiting IL-36γ activity as the new therapeutic option of acute lung injury.

IL-36γ and innate immunity

As IL-36 subfamily members, IL-36α, IL-36β, IL-36γ, IL-38 and IL-36RA are known. IL-36α, IL-36β, and IL-36γ were previously named as IL-1F6, IL-1F8, and IL-1F9[5]. These all members bind to IL-36R and form signal complex with IL-1R accessory protein (AcP) as a co-receptor[6]. After that, nuclear factor-κB and mitogen-activated protein kinases (MAPKs) are activated, then leading to activate IL-8 promoter reporter lesion and secretion of IL-6[5,6]. IL-1 family including IL-36 subfamily generally mediates innate immunity, and IL-36 subfamily is known to be involved in antiviral innate immunity[7]. And IL-36RA acts as receptor antagonist[7]. For innate immunity, human macrophages constitutively product IL-36β and IL-36RA[5,7,8], but IL-36γ expression is increased by TLR stimulation[5,7]. For example, stimulation with ligands for TLR2 and TLR4 induced IL-36γ production in human monocyte line[8]. IL-36γ is produced by keratinocytes, intestinal epithelial cells, bronchial epithelial cells, alveolar macrophage, and mononuclear cells[7]. And another previous paper using IL-36γ knock out mouse showed that deletion of IL-36γ or IL-36R resulted in Pseudomonas aeruginosa–induced attenuated lung injury[9]. In that report, IL-36α and IL-36γ were released from alveolar macrophages and pulmonary epithelial cells[9].

IL-36γ and infectious pulmonary diseases

Already, many scientific reports about IL-36γ related inflammation has been published, but number of reports about IL-36γ and infectious pulmonary diseases is not sufficient, yet. Therefore mechanism of IL-36γ mediating lung inflammation is not well elucidated, and further study would be necessary. In those situation, several research papers were already discussed about IL-36γ mediating lung inflammation.

IL-36γ stimulates proliferation of native CD4 cells and IL-2 production. IL-36γ in bronchial alveolar lavage fluid was report to be elevated with mycoplasma pneumonia patients[10]. In several kinds of viral or bacterial pulmonary infectious experiments, IL-17 stimulates IL-36γ production in bronchial epithelial cell[11,12], and IL-36γ also induces IL-8 and Th17 chemokine, which is promoting neutrophilic airway inflammation via activating lung fibroblast[11,13].

IL-36γ deficiency, either by genetic deletion or by antibody neutralization, resulted in significantly increased mortality during Streptococcus pneumoniae-induced pneumonia animal model[14]. And IL-36γ deficiency impaired lung bacterial clearance during Klebsiellae pneumonia-induced pneumonia animal model[14]. On the other hand, IL-38 has recently also been described to act as an antagonist for IL-36R in an Aspergillus infection model mouse[15]. These facts that IL-36 subfamily respond to inflammatory stimuli induced by infections suggesting role of IL-36 subfamily in anti-microbial inflammation.

In psoriasis patients, serum IL-36γ level is already reported to be elevated and correlated with disease activity, and IL-36γ is a potential biomarker for the treatment of psoriasis[16]. We suppose that it might be promising with inflammatory lung disease, but there are very little reports describing about IL-36γ as the biomarker for human lung disease. One research reported that IL-36γ mRNA level in biopsies was correlated with severity in recurrent respiratory papillomatosis[17].The role of IL-36γ in inflammatory pulmonary diseases is under investigation.

Anti-IL-36γ therapy and future direction

Under the consideration of above description, IL-36γ involves in neutrophilic lung injury. And IL-36γ might have a possibility to be the candidate for biomarker of pulmonary diseases and infectious diseases. On the other hand, inhibiting IL-36γ activity might lead to suppress lung inflammation in acute lung injury. For example, IL-36RA and IL-38 inhibits IL-36R activity are associated with IL-1RacP[18]. So administration of IL-36RA of inhibiting of IL-1RcP might suppress IL-36γ activity.

One candidate for therapeutic option is neutralization of IL-36γ or IL-36R. And another candidate is neutrophil-derived protease antagonist[19]. Since, neutrophil-derived cathepsin G and elastase are potent IL-36-activating enzymes, and IL-36γ must be cleaved at the N-terminus to become active form[19]. Recently, Suliva GP et al showed that neutrophil-derived proteases antagonist suppressed activation of IL-36 subfamily cytokines and related inflammation[20]. They might be less having adverse effect compared with anti-IL-36γ antibody and/or anti-36R antibody, when trying clinical trial for pneumonia patients.

Taken together, IL-36γ plays an important role for pulmonary infections, and authors suppose that inhibiting IL-36γ activity has a possibility to act as therapeutic option for lung injury. However, accumulation of scientific evidence at laboratory would be necessary before putting into practice at bedside. And we can pay attention for the future of IL-36γ related research work.


Yasuyuki Taooka thanks Megumi, Shintaro, and Kohei Taooka for their help. Author's contributions: All authors contributed in critiquing the manuscript. All authors have read and approved the final manuscript.

List of abbreviations: Interleukin (IL), receptor antagonist (RA), IL-1R accessory protein (IL-1RAcp), Immunoglobulin (Ig), Toll-like receptor (TLR), Immunoglobulin (Ig), three Ig domain-containing IL-1R related-1 (TIGIRR-1).


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