Skip Ribbon Commands
Skip to main content

Title

The anti-inflammatory and anti-cancer roles/mechanisms of interleukin-37 and its receptors.

Project Description

The momentous discovery of the interleukin(IL)-1 family that induce inflammation revolutionized our understanding of cancer over three decades ago, yet a relatively new IL-1 family member, called IL-37, actually downregulates inflammation and represents an exciting new frontier under investigation here. IL-37 both blocks the pro-inflammatory activity of IL-18 by competing for the IL-18Rα receptor, but IL-37 is also proposed to signal through a co-receptor, TIR8, via the IL-37/IL-18Rα/TIR8 ternary complex.  This dual mechanism of IL-37 activities makes IL-37 a potent anti-inflammatory molecule and, considering the clinical success of IL-1 family thus far, IL-37 itself be an idea candidate for a newly developed therapeutic that blocks multiple inflammatory disorders, including cancer.  Our novel approach combines biochemical, biophysical, and biological studies to address the particular active forms of IL-37 (Aim 1) and then reveal how IL-37 interacts with its receptors (Aim 2).   In Aim 1, we will determine the minimum IL-37 sequence responsible for its anti-inflammatory activities as well as compare the activities of the biologically found forms. To this end, we have developed a novel recombinant expression system that allows for the production of milligram quantities of IL-37 and will be used to produce a series of IL-37 constructs. The structural integrities of these proposed IL-37 constructs will be assessed by Nuclear Magnetic Resonance and their anti-inflammatory activities will be quantified using cell-based assays that monitor both downstream signaling and phenotypical changes.  In Aim 2, we will characterize the binding of IL-37 to both IL-18Rα and TIR8. Both biochemical and biophysical experiments will be used to define the interactions of IL-37 constructs and its receptors, thereby determining their respective affinities and the sequence of binding events. Already, mammalian and bacterial expression systems are in place for both IL-18Rα and TIR8, respectively, along with preliminary results that confirm our recombinant proteins interact tightly.

Area of Study

Hematology and Oncology; Immunology and Autoimmune Diseases

Populations

 

Method

Biomolecular Structure and Biochemistry; Cell Biology, Molecular Biology, and Genetics

Disease or Symptom

Cancer; Immune Related Disease

Department

Biochemistry and Molecular Genetics

Mentor Location

RC-1 South 9-117

Mentor Contact Number

917-572-2649

Mentor Email

Elan.Eisenmesser@ucdenver.edu

Website

http://www.ucdenver.edu/academics/colleges/medicalschool/departments/biochemistry/Faculty/PrimaryFaculty/Pages/Eisenmesser.aspx

Mentor Name

Eisenmesser, Elan

Funding Department/Program

Cancer Center

Status

Current

Display on public listing?

Yes

Upload Date

8/18/2015 10:16 AM

Attachments

Created at 8/21/2015 7:53 AM by Ross, Randy
Last modified at 11/6/2018 10:41 AM by Zoghby, Caitlin