Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus

Arthritis Rheumatol. 2015 Dec;67(12):3219-25. doi: 10.1002/art.39328.


Objective: Knowledge of interleukin-38 (IL-38), formerly IL-1 family member 10, is sparse, but Il1f10 polymorphisms are associated with inflammatory diseases, and recombinant IL-38 inhibits inflammatory responses similar to those reported in the context of systemic lupus erythematosus (SLE). We undertook this study to explore the function of endogenous IL-38 in human peripheral blood mononuclear cells (PBMCs) as well as its abundance in serum in a well-characterized cohort of SLE patients.

Methods: Serum IL-38 and IL-10 levels were quantified by enzyme-linked immunosorbent assay in 142 SLE patients at ≤3 consecutive visits and in 28 healthy volunteers. To assess IL-38 function, we silenced IL-38 in PBMCs from healthy donors using IL-38 small interfering RNA (siRNA).

Results: IL-38 (63-5,928 pg/ml) was detectable in 16% of 372 serum samples. IL-38 abundance was significantly higher in samples from SLE patients than in samples from healthy controls (P = 0.004) and 11-fold higher in patients with active disease (SLE Disease Activity Index 2000 [SLEDAI-2K] score of ≥4) than in those with inactive disease (SLEDAI-2K score of <4) (P = 0.044). Importantly, IL-38 detection was associated with increased risk of renal lupus (relative risk [RR] 1.6, P = 0.027) and central nervous system lupus (RR 2.3, P = 0.034), and detectable baseline IL-38 entailed a 1.6-fold increased risk of subsequently meeting criteria for persistently active disease (P = 0.0097). Longitudinal time-adjusted mean IL-38 concentration was also 6-fold higher in patients with persistently active disease than in those without (P = 0.023). Remarkably, PBMCs treated with IL-38 siRNA produced up to 28-fold more of the proinflammatory mediators IL-6, CCL2, and APRIL than did control siRNA-transfected cells upon stimulation with Toll-like receptor agonists. Similarly, in SLE patients, the antiinflammatory cytokine IL-10 was 5-fold more abundant when IL-38 was detectable.

Conclusion: This is the first study of the function of endogenous IL-38, and the data suggest that IL-38 may be protective in SLE. A strong association between IL-38 and SLE severity suggests that IL-38 expression is driven by processes linked to SLE pathogenesis. Exploitation of the regulatory effects of IL-38 may represent a promising therapeutic strategy in SLE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Chemokine CCL2 / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Inflammation
  • Interleukin-10 / immunology
  • Interleukin-6 / immunology
  • Interleukins / immunology*
  • Leukocytes, Mononuclear / immunology*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Nephritis / immunology
  • Male
  • Middle Aged
  • RNA, Small Interfering
  • Severity of Illness Index
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / immunology
  • Young Adult


  • CCL2 protein, human
  • Chemokine CCL2
  • IL-38 protein, human
  • IL10 protein, human
  • IL6 protein, human
  • Interleukin-6
  • Interleukins
  • RNA, Small Interfering
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Interleukin-10