Inflammation’s trigger finger

A molecule found in nearly all cells plays a vital role in kick-starting the production of key biological molecules involved in inflammation, a group of Salk Institute scientists has discovered. The finding, published in the June 25 issue of Science, may lead to new strategies for blocking the devastating inflammation that lies at the heart of autoimmune disorders such as multiple sclerosis, arthritis, lupus as well as some cancers.

When the cells of the body are confronted with toxic chemicals or disease-causing organisms, such as viruses and bacteria, the immune system mobilizes rapidly to produce an inflammatory response. This army of chemical and cellular defenses is unleashed through a complex chain of molecular events, triggered by master control proteins. These control proteins act as recruiting officers, rallying other proteins to set up the inflammatory defense. One of the most important molecular sergeants is a protein called nuclear factor-kappa B (NF-kB), which can order the production of scores of defensive proteins.

But NF-kB can’t work alone; it requires the help of a complicated complex of other proteins. A team of scientists which included Jeanette Ducut Sigalla, Virgine Bottero and Inder Verma from the Salk Institute together with colleagues from CellGene found that a protein called ELKS is a crucial member of this complex. Verma’s team determined that when ELKS was missing, NF-kB was unable to activate the production of proteins involved in inflammation.

“NF-kB is a major cell survival signaling molecule, but it needs to be induced,” said Verma. “It normally is found in an inactive form in nearly all cells, but in response to external signals, encourages inflammatory responses and only triggers those responses when it receives the right messages. ELKS is one of the essential component of the complex, without which NF-kB can’t function.”

Inflammation is central to the body’s generalized defensive response, attacking any invader in the same way by boosting blood flow and recruiting specialized cells to attack and destroy the invading organisms. In some diseases, however, the immune system misfires and attacks the body, inflaming nerve, liver, muscle and other cells.

Because of its central role in initiating inflammation, NF-kB is being intensely scrutinized by pharmaceutical researchers looking for new therapies for autoimmune diseases like lupus and arthritis, and other diseases such as cancer. However, it is a difficult target for drug intervention because it is a vital component of most cells in the body; curbing its activity could kill all cells, including healthy ones. Verma and his group hope that by pinpointing other molecules that help NF-kB do its job, they may find new ways of stopping inappropriate inflammation.