Table 1.

Recent evidence and potential mechanisms of IL-38 in infections

Pathogenic diseases	Models	Expression and regulation of IL-38		References
Influenza	Human study and animal model	Increased IL-38 levels in patients with influenza, returned to baseline once recovered.	IL-38 counteracts the proinflammatory effects of IL-36α.	Gao et al. [4]
COVID-19	Human study and animal model	Increased IL-38 levels in patients with SARS-CoV-2, negatively correlated with disease severity.
	Human study	IL-38 levels were not influenced by COVID-19, disease severity, sex, age, or chronic disease, while obese people showed lower IL-38 levels. These parameters have concurrent impacts on IL-38 levels.		Al-Bassam et al. [5]
Chronic hepatitis B	Human study	Decreased levels of IL-38 in HBV infection patients, and IL-38 was assumed to be pathogenic in the case of HBV infection.		Alaaraji [6]
	Human study	Increased IL-38 levels in chronic hepatitis B patients, and IL-38 served as a biomarker of liver damage and positive virological response to antiviral treatment.		Wang et al. [7]
HCV infection	Human study	Higher IL-38 levels in treated HCV infection patients and healthy individuals than in pretreated patients; patients with higher IL-38 levels showed reduced liver injury.		Fazeli et al. [8]
Fungal infection	Cell model	IL-38 inhibited C. albicans-induced Th17 cytokine production.		Van de Veerdonk et al. [2]
Sepsis	Human study and animal model	Elevated IL-38 levels correlated negatively with IL-6 and TNF-α levels in sepsis; exogenous IL-38 improved survival of septic mice.		Xu et al. [11]
	Animal model	Increased IL-38 levels were produced by CD4 + CD25 + Treg cells and, in turn, increased survival of septic mice by enhancing production of IL-10, TGF-β1 and Tregs.		Ge et al. [12]
	Animal model	IL-38 promoted M2 macrophage polarization, inhibited macrophage apoptosis, and suppressed NLRP3 inflammasome activation in macrophages.		Ge et al. [13]
ARDS	Human study, animal model and cell model	Elevated IL-38 levels in ARDS; IL-38 protected from ARDS by inhibiting the differentiation of Th17 cells.		Chai et al. [14]
Trained immunity	Human study, animal model and cell model	IL-38 prevented the proinflammatory epigenetic reprogramming in the subsequent response to secondary stimulation by LPS. SNP rs5896312 affected both plasma IL-38 levels and the inducibility of trained immunity in monocytes.		de Graaf et al. [15]