Lowly Cytokine May Play Role In Controlling Neurotransmitters

March 28, 2002

More interesting research. TNF-a was one of the immune abnormalities (in

autism) that Dr. Griffith discussed during the last Video conference.

If I remember correctly, she said that research had found elevated levels.

Cheryl

Ohio State University

23-Mar-02

http://www.newswise.com/articles/2002/3/TNF.OSU.html

Lowly Cytokine May Play Role In Controlling Neurotransmitters

Library: MED

Keywords: CYTOKINE IMMUNE CENTRAL NERVOUS SYSTEM NEUROTRANSMITTER

Description: Researchers have discovered that a protein normally thought

only to be a component in the immune system actually plays a key role in

regulating neurotransmission in the central nervous system as well.

(Science, Mar-2002)

LOWLY CYTOKINE MAY PLAY ROLE IN CONTROLLING NEUROTRANSMITTERS

COLUMBUS, Ohio -- Researchers here in collaboration with a group in

California have discovered that a protein normally thought only to be a

component in the immune system actually plays a key role in regulating

neurotransmission in the central nervous system -- the CNS -- as well.

The protein, tumor necrosis factor alpha, or TNF-alpha, has long been known

to be a key player in controlling cell death but this new finding offers new

insights into how cells interact within the human nervous system.

Understanding this new role of TNF-alpha may provide researchers with

possible new approaches to treating illnesses such as dementia, Alzheimer's

disease, stroke, epilepsy and spinal cord injury. The report was published

in the latest issue of the journal Science.

The findings by Bresnahan, professor of neurosciences at Ohio

State University; Beattie, professor and chair of the same

department, and colleagues at Stanford University, show that TNF-alpha is

vital for controlling the strength of signal transmission between nerve

cells. And the level of signal strength may play an important role in

determining how nerve cells respond to injury.

Researchers have long believed that neurons were the most important cells in

the nervous system because they controlled the passage of signals throughout

the CNS. They thought that glial cells -- astrocytes, oligodendrocytes and

microglia -- only performed a support role for those neurons, providing

oxygen and nutrients to the neurons, shielding neurons from each other, and

basically cleaning up dead neurons.

The new research, however, points to a much greater role for the glial cells

since they can manufacture and release TNF-alpha into the CNS environment.

The TNF-alpha apparently is able to regulate the expression of certain

neurotransmitter receptors on the surface of neurons. The more of these

receptors there are on the surface of the neuron, the more signals it can

transmit.

In this case, the signals arise from the binding of glutamate molecules from

the fluid surrounding the cell to these receptors. When the glutamate and

receptor meet, a nerve impulse, or signal, is produced. The more receptors

present, the more signals are increased.

Normally, the cytokine TNF-alpha is released as part of the inflammatory

process following an injury to the cells. Based on discussions with other

Ohio State colleagues on how the brainstem sends " nausea signals " to the

stomach, Beattie and Bresnahan remembered that when TNF-alpha and glutamate

are both present, cell signaling activity seemed to increase.

" We wondered that since there was glutamate and TNF-alpha present in the

spinal cord after injury, then maybe TNF-alpha is actually enhancing the

killing effect of the normal neurotransmitter, " Beattie said.

In testing this, they exposed nerve cells first to glutamate and then to

TNF-alpha. Separately, neither had an impact on the normal killing effect.

But when they exposed the cells to even small amounts of both compounds, the

killing effect increased 120 percent.

" This was a complete surprise and validated our hypothesis, " Bresnahan said.

The real question, however, was in the details of the process -- how exactly

was the killing effect enhanced. For help with the answer, they turned to

Beattie's brother , a post-doctoral researcher at Stanford. The lab in

which Beattie was conducting research was looking at the role glutamate

played in signal transmission in learning and memory.

" We wanted to know if TNF-alpha was regulating the number of receptors on

the cell surface, " Bresnahan explained. " If the number of receptors

increased, and if there was glutamate nearby to bind to them, that would

allow more calcium into the cells, killing them. "

Experiments at the Stanford lab were able to show that controlling the

presence or activity of TNF-alpha had a direct relationship to the numbers

of glutamate receptors on the cell surface and therefore on the amount of

synaptic transmission.

" This showed that TNF-alpha, this cytokine that is supposed to come from the

immune system and not have a role in transmitting information, is actually a

potent modulator of neurotransmitter interaction, " Beattie said.

Beattie and Bresnahan's work has now turned to how this process affects the

speed at which nerve cells die, adding that a host of illnesses are caused

by a degeneration of neurons.

Their work was supported by grants from the National Institutes of Health.

#

Contact:

Beattie, (614) 688-8327; beattie.2@...

Bresnahan, (614) 292-2206; bresnahan.1@...

_________________________________________________________________

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March 28, 2002

Cheryl,

It was Dr Jyonouchi, you are right about TNF-a being elevated for some.

Jon.

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1: J Neuroimmunol 2001 Nov 1;120(1-2):170-9

Proinflammatory and regulatory cytokine production associated with innate and

adaptive immune responses in children with autism spectrum disorders and

developmental regression.

Jyonouchi H, Sun S, Le H.

Department of Pediatrics, University of Minnesota, MMC 610 FUMC, 420 Delaware

Street SE, Minneapolis, MN 55455, USA. jyono001@...

We determined innate and adaptive immune responses in children with

developmental regression and autism spectrum disorders (ASD, N=71),

developmentally normal siblings (N=23), and controls (N=17). With

lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood

mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above

the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by

control PBMCs. ASD PBMCs produced higher levels of

proinflammatory/counter-regulatory cytokines without stimuli than controls. With

stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from

47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha

depending on stimulants. Our results indicate excessive innate immune responses

in a number of ASD children that may be most evident in TNF-alpha production.

PMID: 11694332 [PubMed - indexed for MEDLINE]