IL-38, a potential therapeutic agent for lupus, inhibits lupus progression

Inflamm Res. 2022 Aug;71(7-8):963-975. doi: 10.1007/s00011-022-01581-3. Epub 2022 Jul 1.

Abstract

Background: Previous studies reported that IL-38 was abnormally expressed in patients with systemic lupus erythematosus (SLE). However, the involvement of IL-38 in the pathophysiology of SLE remains unknown.

Methods: The therapeutic potential of IL-38 was tested in pristane-treated wild-type (WT) and IL-38-/- mice. Thus, SLE was induced via pristane in WT and IL-38-/- mice. Afterwards, the liver, spleen, and kidney of each mouse were obtained. The flow cytometric analysis of the immune cells, serologic expression of inflammatory cytokines and autoantibodies, renal histopathology, and inflammatory signaling were evaluated.

Results: WT mice with pristane-induced lupus exhibited hepatomegaly, splenomegaly, severe kidney damages, increased lymphoproliferation, enhanced lymphoproliferation, and upregulated inflammatory cytokines, such as IL-6, IL-13, IL-17A, MIP-3α, IL-12p70, and IFNγ, and elevated levels of autoantibodies, such as ANA IgG, anti-dsDNA IgG, and total IgG. IL-38-/- mice whose lupus progressed, had elevated cells of CD14+, CD19+, CD3+, and Th1, upregulated inflammatory cytokines and autoantibodies, and severe pathological changes in kidney. Administration of recombinant murine IL-38 to pristane-treated IL-38-/- mice improved their renal histopathology, which depended on ERK1/2, JNK1/2, p38, NF-κB p65, and STAT5 signaling pathways.

Conclusion: IL-38 regulates SLE pathogenesis. Furthermore, targeting IL-38 is critical in the treatment of SLE.

Keywords: Autoimmunity; IL-38; Immune response; Inflammation; Lupus.

MeSH terms

  • Animals
  • Autoantibodies / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Immunoglobulin G
  • Immunologic Factors / therapeutic use
  • Interleukin-1 / metabolism*
  • Lupus Erythematosus, Systemic* / drug therapy
  • Mice
  • Terpenes

Substances

  • Autoantibodies
  • Cytokines
  • Il1f10 protein, mouse
  • Immunoglobulin G
  • Immunologic Factors
  • Interleukin-1
  • Terpenes