Correlation Between Early Plasma Interleukin 37 Responses With Low Inflammatory Cytokine Levels and Benign Clinical Outcomes in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

J Infect Dis. 2021 Feb 24;223(4):568-580. doi: 10.1093/infdis/jiaa713.


Background: The immune protective mechanisms during severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remain to be deciphered for the development of an effective intervention approach.

Methods: We examined early responses of interleukin 37 (IL-37), a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients before any clinical intervention and determined its correlation with clinical prognosis.

Results: Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses were correlated with earlier viral RNA negative conversion, chest computed tomographic improvement, and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower interleukin 6 and interleukin 8 (IL-8) and higher interferon α responses and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and C-reactive protein. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2-transgenic mice infected with SARS-CoV-2.

Conclusions: Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I interferon, thereby maintaining the functionalities of vital organs. IL-37, IL-8, and C-reactive protein might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.

Keywords: COVID-19; IL-37; SARS-CoV-2; clinical outcomes; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • C-Reactive Protein / metabolism
  • COVID-19 / blood
  • COVID-19 / immunology*
  • Cytokine Release Syndrome / virology*
  • Female
  • Humans
  • Inflammation / immunology
  • Inflammation / virology
  • Interleukin-1 / blood*
  • Interleukin-8 / blood
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged


  • CXCL8 protein, human
  • IL37 protein, human
  • Interleukin-1
  • Interleukin-8
  • C-Reactive Protein