Interleukin-37 monomer is the active form for reducing innate immunity

Proceedings of the National Academy of Sciences of the United States of America
Elan Z EisenmesserCharles A Dinarello

Abstract

Interleukin-37 (IL-37), a member of the IL-1 family of cytokines, is a fundamental suppressor of innate and acquired immunities. Here, we used an integrative approach that combines biophysical, biochemical, and biological studies to elucidate the unique characteristics of IL-37. Our studies reveal that single amino acid mutations at the IL-37 dimer interface that result in the stable formation of IL-37 monomers also remain monomeric at high micromolar concentrations and that these monomeric IL-37 forms comprise higher antiinflammatory activities than native IL-37 on multiple cell types. We find that, because native IL-37 forms dimers with nanomolar affinity, higher IL-37 only weakly suppresses downstream markers of inflammation whereas lower concentrations are more effective. We further show that IL-37 is a heparin binding protein that modulates this self-association and that the IL-37 dimers must block the activity of the IL-37 monomer. Specifically, native IL-37 at 2.5 nM reduces lipopolysaccharide (LPS)-induced vascular cell adhesion molecule (VCAM) protein levels by ∼50%, whereas the monomeric D73K mutant reduced VCAM by 90% at the same concentration. Compared with other members of the IL-1 family, both the N and the C term...Continue Reading

References

Dec 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·P E AuronC A Dinarello
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Nov 21, 2007·Biophysical Journal·Mario de Oliveira NetoIgor Polikarpov
Mar 26, 2009·Protein Science : a Publication of the Protein Society·Jennifer SchlegelElan Zohar Eisenmesser
Jun 9, 2009·Journal of Molecular Biology·Jennifer SchlegelElan Zohar Eisenmesser
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Aug 31, 2010·Nature Immunology·Dongli WangXinquan Wang
Sep 18, 2010·Cytokine & Growth Factor Reviews·Alexander Zdanov
Jul 19, 2013·The Journal of Biological Chemistry·Krishna Mohan PoluriKrishna Rajarathnam
Nov 19, 2013·Seminars in Immunology·Cecilia GarlandaAlberto Mantovani
Nov 28, 2013·Seminars in Immunology·Charles A Dinarello, Jos W M van der Meer
Jan 21, 2014·Protein Science : a Publication of the Protein Society·Agnieszka A KendrickElan Z Eisenmesser
May 17, 2014·Journal of Biomolecular NMR·Oliver F Lange
Dec 17, 2014·Nature Communications·Naotaka TsutsumiZenichiro Kato
Feb 25, 2015·Immunology and Cell Biology·Irina KufarevaTracy M Handel
Aug 13, 2015·Autoimmunity Reviews·Wang-Dong XuYi Liu
Nov 10, 2015·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Libin YangTan Lu
Jan 23, 2016·Journal of Experimental & Clinical Cancer Research : CR·Guanqun GeYan Xue
Jun 3, 2016·Medical Oncology·Vivi A DingYujiang Fang
Aug 5, 2017·International Journal of Molecular Sciences·Sarah ThompsonSimi Ali
Aug 8, 2017·Science Immunology·Andrew M EllisdonMarcel F Nold
Feb 20, 2018·Current Opinion in Structural Biology·Lena Kjellén, Ulf Lindahl

❮ Previous
Next ❯

Citations

Mar 4, 2020·Journal of Leukocyte Biology·Yu MeiHaiyan Liu
Aug 15, 2020·Journal of Cellular Physiology·Alessandra VecchiéAntonio Abbate
Aug 1, 2019·International Journal of Molecular Sciences·Theoharis C TheoharidesPio Conti
Sep 14, 2019·Nature Reviews. Rheumatology·Charles Anthony Dinarello
Feb 23, 2020·Clinical Reviews in Allergy & Immunology·Daniel Elieh Ali KomiIan M Adcock
Oct 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Irene TsilioniTheoharis C Theoharides
Jun 21, 2020·International Journal of Molecular Sciences·Pio ContiGianpaolo Ronconi
Nov 2, 2020·Joint, Bone, Spine : Revue Du Rhumatisme·Viola KlückLeo A B Joosten
Oct 2, 2020·Brain, Behavior, and Immunity·Jesus Amo-AparicioRuben Lopez-Vales
Mar 9, 2021·Frontiers in Cellular and Infection Microbiology·Ashleigh R Murphy-Schafer, Silke Paust
Apr 3, 2021·Frontiers in Immunology·Praxedis MartinGaby Palmer
Apr 7, 2021·The Journal of Biological Chemistry·Suzhao LiCharles A Dinarello
Jul 13, 2021·Frontiers in Immunology·Zhangci Su, Xiaoan Tao

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.