Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Novel insights into the role of anti-inflammatory IL-38 in immunity against infection

Cellular & Molecular Immunology volume 19, pages 1322–1324 (2022)Cite this article

Subjects

The Original Article was published on 23 October 2019

This article has been updated

Since the identification and cloning of interleukin (IL)-38 in 2001, a plethora of studies have focused on its essential roles as a novel IL-1 family cytokine in both innate and acquired immunity. Based on the shared traits with IL-36 receptor antagonist (IL-36Ra) and IL-1 receptor antagonist (IL-1Ra), IL-38 constitutes one of the most important anti-inflammatory cytokines within the IL-36 subfamily and thus elicits its antagonistic effects through binding to IL-36 receptor (IL-36R) and to IL-R1 with a relatively low affinity [1, 2]. IL-38 has been proven to bind to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) [1], and IL1RAPL1 therefore serves as a novel receptor of IL-38. The IL-38 precursor has no signal peptide and is readily released once activated. Notably, released IL-38 requires N-terminal processing to be fully biologically active, and the natural N-terminus of IL-38 has not yet been identified, resulting in the use of several recombinant forms of IL-38 with distinct biological functions. Truncated IL-38 with amino acids 20-152 is widely considered anti-inflammatory [1], albeit the 1-152 amino acid full-length IL-38 is proinflammatory and has been reported to enhance the secretion of inflammatory IL-6 and CXCL8 from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) [1, 2], leading to diverse therapeutic potentials of IL-38 in different types of disease settings. The expression patterns of IL-38 are most prominent in epithelial barrier tissues and immune cells, suggesting a role of IL-38 in protecting these barriers from pathogens. Recent evidence highlighting the involvement of IL-38 in the development of infectious diseases derived from bacterial, virus and fungal infections, together with the proposed regulatory mechanisms, will be discussed in this correspondence.

The critical role of IL-38 in infectious diseases has received widespread attention based on the fact that IL-38 is a universal immunosuppressive cytokine and that infectious diseases are often accompanied by a dysregulated hyperimmune response. Beginning with our study of IL-38 in allergic asthma in 2016, we reported that IL-38 significantly inhibited proinflammatory IL-6, IL-1β, CCL5, tumor necrosis factor (TNF)-α, and Th1-related CXCL10 as well as antiviral interferon (IFN)-β expression in human primary bronchial epithelial cells upon stimulation by the viral RIG-like receptor (RLR) ligand poly (I:C) LyoVec [3], leading to our speculation that IL-38 modulates infectious diseases. Unlike the activities of IL-36 agonists IL-36α, IL-36β and IL-36γ, which enhance lung inflammation and exacerbate lung injury in pulmonary infections, we have proposed that IL-38 can counteract the biological activities of IL-36 signaling [4]. Although IL-38 was barely detectable in healthy lung tissue, it was enriched in viral-related TLR3 ligand poly(I:C)-induced lung injury, a model mimicking respiratory viral infections. Subsequently, IL-38 expression was found to be significantly increased in patients hospitalized with influenza A/B or SARS-CoV-2 infection, and its level was negatively correlated with disease severity [4]. A recent study demonstrated that circulating IL-38 levels were not affected by COVID-19, disease severity, age, sex, or comorbidity with chronic disease in each stratum, while obese patients showed lower IL-38 levels [5]. Otherwise, those parameters seem to have concurrent impacts on IL-38 levels, as female patients showed higher IL-38 levels than male patients in severe disease subgroups, and older patients showed higher IL-38 levels than patients <50 years old in critical disease subgroups [5]. Consistent with our studies, they showed that moderate disease patients tended to have higher IL-38 levels than severe or critical disease patients [5]. Sample size, as well different ELISA kits used in different studies, may account for the contradictory parts among the investigations. Apart from the lung, the liver is the second most studied organ for the role of IL-38 in viral infections. In chronic hepatitis B, Alaaraji SF detected lower levels of IL-38 in hepatitis B virus (HBV)-infected patients, and IL-38 was thought to be pathogenic in the context of HBV infection [6]. Wang et al., however, detected higher IL-38 levels in chronic hepatitis B individuals [7]. Although the exact mechanism of the phenomenon has not been elucidated, the baseline IL-38 concentrations were associated with persistent liver damage in untreated individuals, and a higher level of serum IL-38 at baseline was associated with a greater probability of virological response to telbivudine treatment. Therefore, baseline serum IL-38 levels in patients with CHB may serve as a biomarker for the outcome of ongoing liver injury and positive antiviral therapy [7]. The changes in IL-38 levels are suggested to play a role in HBV infection, based on these limited data. However, whether IL-38 is beneficial or detrimental may depend on the stage of the disease, the form and the dose of the applied IL-38, and in this regard, an animal model with IL-38 knockout mice will help elucidate the regulation of IL-38 in HBV infection. Of note, a recent article reported statistically higher IL-38 levels in treated hepatitis C virus (HCV)-infected patients and healthy individuals than in pretreated patients and that patients with higher IL-38 levels had lower alkaline phosphatase (ALP) levels and thus reduced liver injury [8], thereby implying a reduction in the IL-38 response in HCV-induced inflammation. However, it is unclear whether the IL-38 response contributes to or reverses the progression of HCV infection, which warrants future studies in animal models (Table 1).

Table 1 Recent evidence and potential mechanisms of IL-38 in infections
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Change history

  • 21 March 2025

    Bi-directional link was added.

References

  1. Mora J, Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, et al. Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses. J Mol Cell Biol. 2016;8:426–38.

    Article  CAS  PubMed  Google Scholar 

  2. van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, et al. Il-38 binds to the il-36 receptor and has biological effects on immune cells similar to il-36 receptor antagonist. Proc Natl Acad Sci USA. 2012;109:3001–5.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sun X, Hou T, Cheung E, Iu TN, Tam VW, Chu IM, et al. Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma. Cell Mol Immunol. 2020;17:631–46.

    Article  CAS  PubMed  Google Scholar 

  4. Gao X, Chan P, Lui G, Hui D, Chu IM, Sun X, et al. Interleukin-38 ameliorates poly(i:C) induced lung inflammation: Therapeutic implications in respiratory viral infections. Cell Death Dis. 2021;12:53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Al-Bassam WW, Al-Karaawi IA, Sharquie IK, Ad’hiah AH. Evaluation of interleukin-38 levels in serum of patients with coronavirus disease 2019. J Med Virol. 2022. https://doi.org/10.1002/jmv.27762. Online ahead of print.

  6. Alaaraji SFT. Exploration of the relationship between interleukins 17, 37 and 38 with vitamin e in iraqi men with chb. Phys: Conf Ser. 2019;1294:052047.

    CAS  Google Scholar 

  7. Wang HJ, Jiang YF, Wang XR, Zhang ML, Gao PJ. Elevated serum interleukin-38 level at baseline predicts virological response in telbivudine-treated patients with chronic hepatitis b. World J Gastroenterol. 2016;22:4529–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fazeli P, Saeidnia M, Erfani M, Kalani M. An overview of the biological and multifunctional roles of il-38 in different infectious diseases and covid-19. Immunol Res. 2022:1–9. https://doi.org/10.1007/s12026-022-09275-y. Online ahead of print.

  9. Gresnigt MS, Rösler B, Jacobs CW, Becker KL, Joosten LA, van der Meer JW, et al. The il-36 receptor pathway regulates aspergillus fumigatus-induced th1 and th17 responses. Eur J Immunol. 2013;43:416–26.

    Article  CAS  PubMed  Google Scholar 

  10. Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for c-reactive protein levels. Circulation 2011;123:731–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu F, Lin S, Yan X, Wang C, Tu H, Yin Y, et al. Interleukin 38 protects against lethal sepsis. J Infect Dis. 2018;218:1175–84.

    Article  PubMed  Google Scholar 

  12. Ge Y, Huang M, Wu Y, Dong N, Yao YM. Interleukin-38 protects against sepsis by augmenting immunosuppressive activity of cd4(+) cd25(+) regulatory t cells. J Cell Mol Med. 2020;24:2027–39.

    Article  CAS  PubMed  Google Scholar 

  13. Ge Y, Chen J, Hu Y, Chen X, Huang M. Il-38 alleviates inflammation in sepsis in mice by inhibiting macrophage apoptosis and activation of the nlrp3 inflammasome. Mediators Inflamm. 2021;2021:6370911.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chai YS, Lin SH, Zhang M, Deng L, Chen Y, Xie K, et al. Il-38 is a biomarker for acute respiratory distress syndrome in humans and down-regulates th17 differentiation in vivo. Clin Immunol. 2020;210:108315.

    Article  CAS  PubMed  Google Scholar 

  15. de Graaf DM, Teufel LU, van de Veerdonk FL, Joosten L, Netea MG, Dinarello CA, et al. Il-38 prevents induction of trained immunity by inhibition of mtor signaling. J Leukoc Biol. 2021;110:907–15.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Innovation and Technology Fund Tier 2 (ref.: PRP/008/21FX), Innovation and Technology Commission, Hong Kong.

Author information

Author notes

  1. These authors contributed equally: Xun Gao, Guoqiu Wu.

Authors and Affiliations

  1. Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China

    Xun Gao, Miranda Sin-Man Tsang, Danqi Huang & Chun Kwok Wong

  2. Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, China

    Xun Gao & Guoqiu Wu

  3. Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China

    Miranda Sin-Man Tsang & Chun Kwok Wong

  4. Faculty of Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China

    Christopher Wai-Kei Lam

  5. Li Dak Sum Yip Yio Chin R and D Centre for Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China

    Chun Kwok Wong

Authors
  1. Xun Gao
    View author publications

    Search author on:PubMed Google Scholar

  2. Guoqiu Wu
    View author publications

    Search author on:PubMed Google Scholar

  3. Miranda Sin-Man Tsang
    View author publications

    Search author on:PubMed Google Scholar

  4. Danqi Huang
    View author publications

    Search author on:PubMed Google Scholar

  5. Christopher Wai-Kei Lam
    View author publications

    Search author on:PubMed Google Scholar

  6. Chun Kwok Wong
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Chun Kwok Wong.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, X., Wu, G., Tsang, M.SM. et al. Novel insights into the role of anti-inflammatory IL-38 in immunity against infection. Cell Mol Immunol 19, 1322–1324 (2022). https://doi.org/10.1038/s41423-022-00876-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-022-00876-z

This article is cited by

Search

Advanced search

Quick links