title: Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Hudson Institute of Medical Research and Monash University, Melbourne, Victoria, Australia.
authors: Ina
authors: I
authors: Rudloff
authors: Monash University and Monash Medical Centre, Melbourne, Victoria, Australia.
authors: Jack
authors: J
authors: Godsell
authors: Hudson Institute of Medical Research and Monash University, Melbourne, Victoria, Australia.
authors: Claudia A
authors: CA
authors: Nold-Petry
authors: Monash University and Monash Medical Centre, Melbourne, Victoria, Australia.
authors: James
authors: J
authors: Harris
authors: Monash University and Monash Medical Centre, Melbourne, Victoria, Australia.
authors: Alberta
authors: A
authors: Hoi
authors: Monash University and Monash Medical Centre, Melbourne, Victoria, Australia.
authors: Eric F
authors: EF
authors: Morand
authors: Hudson Institute of Medical Research and Monash University, Melbourne, Victoria, Australia.
authors: Marcel F
authors: MF
authors: Nold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018932:Chemokine CCL2 / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering; D012720:Severity of Illness Index; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology; D055815:Young Adult
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C571243:IL-38 protein, human; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D007378:Interleukins; D034741:RNA, Small Interfering; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D016753:Interleukin-10