Cryopyrin protein responds to invading bacteria by activating of IL-1beta

[Guest guest]

Cryopyrin protein responds to invading bacteria by activating of

IL-1beta

Researchers at the University of Michigan Medical School have

discovered that a protein called cryopyrin responds to invading

bacteria by triggering the activation of a powerful inflammatory

molecule called IL-1beta ( interleukin-1beta ), which signals the

immune system to attack pathogens and induces fever to protect the

body against infection.

The discovery could help researchers understand what causes

autoimmune diseases like rheumatoid arthritis where the immune system

attacks and destroys tissue in the patient's body.

" IL-1beta is a master regulator of infection, and it's known to be

involved in the development of rheumatoid arthritis, " says

Nunez, at U-M Medical School, who directed the research study.

In a study being published in Nature, researchers have shown, for the

first time, that cryopyrin is activated by bacterial RNA and that it

is essential to the cell's ability to mount an effective defense

against bacteria.

Found in the cytosol, cryopyrin is a member of the NOD-LRR family of

proteins, which protect cells against microbial infection. Defective

cryopyrin is predicted to be associated with increased susceptibility

to infection.

Small mutations in CIAS1 – the human gene for cryopyrin – are known

to cause three rare autoinflammatory diseases: familial cold

autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset

multiple-system inflammatory disease. People with these diseases

produce uncontrolled amounts of IL-1beta and other inflammatory

molecules. This causes them to have recurrent episodes of fever and

to develop rashes – often when they are exposed to cold temperatures.

Based on previous research with cell lines, researchers suspected

that cryopyrin was an important link between the immune system's

normal job of killing bacteria and the abnormal development of

autoimmune diseases. But no one was sure exactly how cryopyrin was

" turned on " in living animals or how it stimulated the immune response.

In previous research, the U-M team found that the single-point

mutation in CIAS1 – which causes autoinflammatory syndromes in people

– activates cryopyrin, even when there is no bacterial RNA present in

the cell. " The mutation fools the cell into producing the activated

form of cryopyrin, even when bacteria aren't there, " Nunez says.

To decipher cryopyrin's signal, Thirumala-Devi Kanneganti studied

immune cells called macrophages and several strains of laboratory

mice. One of these strains was unable to produce cryopyrin, because

the CIAS1 gene had been removed.

Kanneganti exposed the macrophages and mice to bacterial RNA and to

small synthetic molecules called R837 ( Imiquimod ) and R848

( Resiquimod ). These adjuvant molecules activate the pro-

inflammatory response in mice and are used as anti-tumor agents and

to treat genital warts caused by a virus in human patients.

" We found that cryopyrin was activated and the macrophages began

secreting IL-1beta following stimulation with R837 or R848, "

Kanneganti says. " Since the structure of these molecules is very

similar to DNA or RNA, we believe the natural ligand, or activating

molecule, for cryopyrin could be DNA or RNA. "

In previous research, other researchers discovered a signaling

pathway in which molecules called toll-like receptors on the cell's

surface recognize invading bacteria and activate the immune response.

But U-M researchers found that cryopyrin uses a different signaling

pathway. Activated cryopyrin triggers an enzyme called caspase-1,

which splits the immature form of IL-1beta to produce the active form

of the molecule. Once IL-1beta is activated, it can be secreted out

of the cell where it binds to the IL-1beta receptor on other cells to

trigger an immune response.

" These two signaling pathways cooperate, " Nunez explains. " The toll-

like receptor pathway recognizes bacteria outside the cell, while

cryopyrin recognizes bacteria that's already in the cell. When a toll

receptor on the membrane senses bacterial RNA, it activates a

signaling pathway called NF-kappaB, which induces the production of

IL-1beta. Cryopyrin does the same thing, but it works through

caspase-1 to produce the active form of IL-1beta. "

In her experiments, Kanneganti confirmed that the signaling pathway

requires the presence of cryopyrin. Macrophages and mice that lacked

the CIAS1 gene for cryopyrin were unable to generate an immune

response when exposed to bacterial products.

Source: University of Michigan Health System, 2006

http://www.xagena.it/news/medicinenews_net_news/

99e5a6ae292728f981127b71861de113.html