Discovery of a naturally occurring compound with potential to treat autoimmune diseases

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"Autoimmune diseases affect almost four percent of the global population, the most common being Crohn’s disease, psoriasis, multiple sclerosis, and rheumatoid arthritis. A new study has identified a naturally occurring compound that may provide a new way of treating these debilitating diseases. ...
One cytokine important to the body’s inflammatory response, interleukin 17 (IL-17), is secreted by a subtype of Th cells called Th17 cells. ...
Researchers started by looking at glycolysis, the metabolic process by which glucose is converted into energy to fuel cells, which is also responsible for creating Th17 cells ...
Glycolysis produces a byproduct called phosphoenolpyruvate (PEP). The researchers discovered that introducing additional PEP into the cells prevented Th17 cells from maturing and inhibited IL-17 production, thereby reducing the body’s inflammatory response. ...

Delving deeper into the process underpinning PEP’s inhibitory action, they found that a protein called JunB promoted Th17 maturation by binding to a specific set of genes. Further experimentation showed that PEP treatment blocked JunB activity, inhibiting the creation of Th17 cells.

Testing what they’d discovered on mice with an autoimmune brain disease, the researchers found that daily administration of PEP stopped the generation of Th17 cells and reduced the Th17-dependent autoimmune response. ..."

"... In the past, researchers who were interested in developing a treatment for autoimmune diseases, often looked at inhibiting glycolysis and thus Th17 cells. But glycolysis is essential to various types of cells in the body and inhibiting it could have significant side-effects. PEP has the potential to be used as a treatment without resulting in such side-effects. ..."

From the highlights and abstract:

"Highlights

• PEP inhibits Th17 generation

• PEP regulates the Th17 transcriptional program

• PEP interacts with JunB and suppresses DNA binding of JunB/BATF/IRF4

• PEP inhibits in vivo Th17 generation and EAE development

Summary

Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates differentiation of autoimmune T helper (Th) 17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not significantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily administration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases."

Discovery of compound with potential to treat autoimmune diseases: Autoimmune diseases such as MS and rheumatoid arthritis affect almost four percent of the global population. A new study has now identified a naturally occurring compound that may provide a new way of treating these debilitating diseases.

Potential treatment of autoimmune diseases revealed in new study Scientists have uncovered a chemical compound that holds potential as a therapeutical for various autoimmune diseases, and they’ve used it to treat mice.

Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity (open access)

Graphical abstract: