Source: Johns Hopkins Medical Institutions     Released: Fri
23-Sep-2005, 08:45 ET

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Key Protein Linked to Transverse Myelitis and Multiple Sclerosis
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JOHNS HOPKINS IL-6 TRANSVERSE MYELITIS MULTIPLE SCLEROSIS
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Hopkins researchers have discovered a single molecule that is a cause
of an autoimmune disease in the central nervous system, called
transverse myelitis (TM), that is related to multiple sclerosis.

Newswise - Hopkins researchers have discovered a single molecule that
is a cause of an autoimmune disease in the central nervous system,
called transverse myelitis (TM), that is related to multiple sclerosis.

In a study published in the October issue of The Journal of Clinical
Investigation, psychiatrist Adam Kaplin, M.D., Ph.D., an assistant
professor at The Johns Hopkins University School of Medicine, and
neurologist Douglas Kerr, M.D., Ph.D., also an assistant professor at
Hopkins, showed that the levels of the protein, IL-6, are dramatically
elevated in the spinal fluid of transverse myelitis (TM) patients.

Although the majority of TM patients suffer a single attack, 15 percent
to 30 percent of patients go on to develop full-blown MS. TM evolves
rapidly and without warning and usually results in permanent
impairment, including weakness of the legs and arms, bowel and bladder
dysfunction, pain and paralysis.

IL-6 is a chemical messenger that cells of the immune system use to
communicate with one another. One of the cell types injured by high
levels of IL-6 includes oligodendrocytes, which help produce the
protective myelin sheath coating around nerve cells. The findings offer
one possible mechanism responsible for demyelinating disorders, such as
TM and MS, and may aid in the development of effective therapies
against these disorders, the researchers say.

"This is the first time a single culprit has been identified as
causing a CNS autoimmune disease," said Kaplin.

The researchers began investigating the protein IL-6 when they became
aware that TM patients suffered from memory impairment and depression.
IL-6 has been implicated in mood and concentration disorders.

"This discovery is a success story that begins with listening
carefully to what patients are telling us about their suffering and
then collaborating across disciplines to open up new avenues of
investigation," said Kaplin.

"TM is related to other autoimmune disorders of the nervous system,
including Guillain-Barré syndrome, MS and acute disseminated
encephalomyelitis. This study may give us a foothold in understanding
all of these disorders and how they are linked together. The benefit
is, therefore, not only to those who are paralyzed by TM, but to those
who have disabilities due to a variety of autoimmune disorders. We are
actively using these findings to aid in developing future diagnostic,
prognostic and therapeutic advancements," said Kerr, director of the
Johns Hopkins Transverse Myelitis Center, the only center devoted to TM
in the world.

Researchers analyzed 42 inflammatory proteins in the cerebrospinal
fluid of both TM and healthy patients. They found that IL-6 was
consistently elevated in TM patients' spinal fluid. Further, the
level of IL-6 directly correlated with the severity of paralysis.

Using cell culture and animal studies, the researchers confirmed that
elevated IL-6 levels were directly injurious to the spinal cord. They
showed that spinal fluid from TM patients induced death of spinal cord
cells when cultured in a dish and that IL-6, when infused in adult
rats, induced paralysis. Under the microscope, tissue from IL-6-infused
rats showed demyelination and injury of axons, pathology that was
nearly identical to that seen in human patients with TM.

Kerr and Kaplin also deduced that the reason IL-6 elevations injure
only the spinal cord and not other regions of the nervous system was
because distinct regions of the nervous system have different responses
to IL-6. They concluded that these different types of responses might
be a part of why different autoimmune disorders of the nervous system
affect distinct regions and cause distinct symptoms.

"When we started, we knew nothing about the bad players in this drama
in the spinal cord of CNS autoimmune diseases - it was a classic murder
mystery and we set out together to find out 'who done it'," said
Kaplin. "We've answered who could have done it, and how, and
where."

Funding for this study was provided by the National Institutes of
Health.
Other investigators involved in this study, conducted solely at
Hopkins, were Deepa M. Deshpande, M.S.; Erick Scott, B.S.; Chitra
Krishnan, M.S.; Jessica S. Carmen, B.S.; Irina Shats, M.S.; Tara
Martinez, B.S.; Jennifer Drummond, B.S.; Sonny Dike, M.D.; Mickail
Pletnikov, M.D., Ph.D.; Sanjay C. Keswani, M.B.; Timothy H. Moran,
Ph.D.; Carlos A. Pardo, M.D., and Peter A. Calabresi, M.D.

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Phytomedicine. 1999 May;6(2):79-84. Related Articles, Links

Inhibitory effect of resveratrol on interleukin 6 release by stimulated
peritoneal macrophages of mice.

Zhong M, Cheng GF, Wang WJ, Guo Y, Zhu XY, Zhang JT.

Institute of Materia Medica, Chinese Academy of Medical Sciences,
Beijing, People's Republic of China.

In the present investigation, interleukin 6 (IL-6) activity in the
supernatant of cultured mouse peritoneal macrophages was monitored
using a sensitive bioassay involving the IL-6-dependent murine
hybridoma B9 cell line. The effects of resveratrol on Il-6 release by
mouse peritoneal macrophages stimulated with calcium ionophore A23187
and fMLP were explored. Resveratrol, at a concentration range from 5 x
10(-6) to 4 x 10(-5) mol.l-1, was found to dose-dependently inhibit
IL-6 release by cultured macrophages induced by A23187 and fMLP, and
showed no direct cytotoxic effect, but induced proliferation of
cultured mouse thymus cells. Resveratrol, at a concentration range from
10(-8) to 10(-5) mol.l-1, was shown to dose-dependently inhibit calcium
ion influx into the cells with the stimulation of fMLP (10(-6)
mol.l-1). These results suggest that the blocking of calcium ion influx
into cells by reveratrol is one of the possible mechanisms of the IL-6
biosynthesis inhibitory action of resveratrol.

PMID: 10374244 [PubMed - indexed for MEDLINE]

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