Treating acute and chronic inflammatory diseases by blocking interleukin-1 beta (IL-12) activity is now part of clinical practice. There are 11 members of the IL-1 family and most induce inflammation. The function of one member, IL-1 family member 7 (IL-1F7), remains elusive. Since its discovery in 2000, there are only 9 papers. Of all members of the IL-1 family, IL-1F7 and IL-18 are the most closely related at the genomic level. There is one report that caspase-1 cleaves the recombinant IL-1F7 precursor and that processed IL-1F7 binds to the IL-18 receptor. However, there is no convincing data that recombinant IL-1F7 exhibits either pro- or anti- inflammatory activities. To avoid difficulties with recombinant forms, we transfected the IL-1F7 precursor into mouse and human cells and observed a profound suppression of endotoxin- and IL-12-induced pro- inflammatory cytokines. Silencing of endogenous IL-1F7 results in higher levels of pro-inflammatory cytokines. Importantly, IL-1F7 translocates to the nucleus. Thus, similar to IL-11 and IL-33, IL-1F7 appears to be a """"""""dual function"""""""" cytokine, that is, functional in the nucleus as well as binding to a cell surface receptor. One hypothesis being tested is whether IL-1F7 binds to the IL-18 receptor and whether such a complex recruits the inhibitory receptor, Single Ig IL-1 Related Receptor (SIGIRR) to suppress cytokines. Another hypothesis being tested is whether the nuclear function of IL-1F7 requires Smad3, the intracellular protein that mediates TGF2 signaling. In addition to testing these hypotheses in cell cultures, we have generated a strain of mice that express human IL-1F7. IL-1F7 transgenic mice are significantly protected against the systemic and local inflammation of endotoxin, dextran sodium sulfate colitis, acute myocardial ischemic infarction and contact antigen sensitization. IL-1F7 now emerges as a major inhibitory cytokine that limits inflammation during innate immune responses. We propose to use these mice to test each of the hypotheses by creating three new strains of mice, each expressing IL-1F7 but deficient in either the IL-18 receptor, SIGIRR or Smad3. The goal of this proposal is to reveal the molecular requirements for the anti-inflammatory activity of IL-1F7. IL-1F7 appears to fill a gap in understanding how the innate immune response is regulated.

Public Health Relevance

of the project is one of human disease in which inflammation plays an important component. Much of inflammation is triggered by small protein molecules called cytokines that act to stimulate genes that cause inflammation. The project seeks to understand how inflammation caused by cytokines is controlled. This information will result in a better understanding of disease severity and possibly new anti-inflammatory therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Aggarwal, Nupur; Korenbaum, Elena; Mahadeva, Ravi et al. (2016) α-Linoleic acid enhances the capacity of α-1 antitrypsin to inhibit lipopolysaccharide-induced IL-1β in human blood neutrophils. Mol Med 22:
Coll-Miró, Marina; Francos-Quijorna, Isaac; Santos-Nogueira, Eva et al. (2016) Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci U S A 113:1411-6
Dinarello, Charles A; Nold-Petry, Claudia; Nold, Marcel et al. (2016) Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol 46:1067-81
Cavalli, Giulio; Koenders, Marije; Kalabokis, Vassili et al. (2016) Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. Rheumatology (Oxford) 55:2220-2229
Shirey, K A; Lai, W; Patel, M C et al. (2016) Novel strategies for targeting innate immune responses to influenza. Mucosal Immunol 9:1173-82
Tzanetakou, Vassiliki; Kanni, Theodora; Giatrakou, Sophia et al. (2016) Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol 152:52-9
Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying et al. (2016) MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proc Natl Acad Sci U S A 113:1363-8
Dinarello, Charles A; Joosten, Leo A B (2016) Inflammation in rheumatology in 2015: New tools to tackle inflammatory arthritis. Nat Rev Rheumatol 12:78-80
Frenzel, Eileen; Wrenger, Sabine; Brügger, Britta et al. (2015) α1-Antitrypsin Combines with Plasma Fatty Acids and Induces Angiopoietin-like Protein 4 Expression. J Immunol 195:3605-16
Bai, Xiyuan; Dinarello, Charles A; Chan, Edward D (2015) The role of interleukin-32 against tuberculosis. Cytokine 76:585-7

Showing the most recent 10 out of 546 publications