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快乐十分玩法与奖金:Interleukin-37 monomer is the active form for reducing innate immunity
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IL-37 is the newest member of the IL-1 family of cytokines that elicit diverse activities integrally related to the innate immune responses and inflammation. Whereas most members elicit proinflammatory responses; in contrast, IL-37 broadly down-regulates inflammation and exists in a unique monomer/dimer equilibrium. Experimental and theoretical analyses show that monomeric IL-37 results in more effective suppression of inflammatory markers on multiple cell types compared with native IL-37, whereas the IL-37 dimer functions to block the activity of the monomer. Considering the emerging efficacy of antagonists and antibodies that specifically target IL-1 in human disease, identifying the active form of IL-37 may lead to the clinical development of recombinant IL-37 to down-regulate inflammation.
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 termini of IL-37 are extended, and we show they are disordered in the context of the free protein. Furthermore, the presence of, at least, one of these extended termini is required for IL-37 suppressive activity. Based on these structural and biological studies, we present a model of IL-37 interactions that accounts for its mechanism in suppressing innate inflammation.
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Author contributions: C.A.D. designed research; E.Z.E., A.G., J.S.R., N.P., T.A., L.Z., R.Z., J.S.K., E.T., X.M., and C.A.D. performed research; J.C.N. collected data; C.A.D. analyzed data; J.C.N. helped with the X-ray data processing; and C.A.D. wrote the paper.
Reviewers: M.M., Humanitas University; and M.W.-W., Ume? University.
The authors declare no conflict of interest.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 6NCU) and in Biological Magnetic Resonance Data Bank (BMRB accession no. 27729).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819672116/-/DCSupplemental.
Published under the PNAS license.