The molecule--leukemia inhibitory factor (LIF)--is the connecting interface between the hypothalamus, the endocrine regulatory center within the brain, and the glands that constitute the endocrine system.

"This is the first documentation of how a novel regulatory cytokine molecule, which is synthesized in the brain, responds and acts appropriately to regulate the release of the pituitary corticotropin (ACTH) hormone, which controls adrenal corticosteroid hormones," explained lead investigator Shlomo Melmed, M.D., director, Cedars-Sinai Research Institute, and senior vice president, Academic Affairs, Cedars-Sinai Medical Center. "LIF acts as an 'on-off' switch, communicating to the endocrine system to produce ACTH, which is secreted by the pituitary to release adrenal steroids. The intrapituitary molecule, suppressor of cytokine signaling (SOCS-3), responds to LIF within the pituitary, allowing very fine tuning of the pituitary response to brain and peripheral signals."

This important discovery, which will be published in the June 7, 1999 issue of Proceedings of the National Academy of Sciences, will provide a tool for researchers studying the endocrine responses that modulate the protection against sepsis (blood-borne infections), shock and inflammation, Dr. Melmed explained. "The stress response to these illnesses protects against the body being overwhelmed by immune or inflammatory insult."

LIF is one of the central triggers from the brain to release hormones in response to acute and chronic illness, trauma, shock, acute and chronic infection and a myriad of other inflammatory conditions, including arthritis and lupus. The endocrine glands function as a control system for the body, with different glands secreting various types of endocrine hormones.

"The adrenal gland's manufacture of corticosteroids (cortisoL) is a classic stress response that is necessary for the body to maintain equilibrium and internal homeostasis," Dr. Melmed said. "We were able to show that the pituitary production of ACTH is regulated by a 'pro-inflammatory cytokine,' LIF, and its pituitary target regulator, SOCS-3."

The research team, which included Cedars-Sinai investigators Corinne Bousquet and Chris Auernhammer, M.D., was able to identify the regulatory structure of SOCS-3, a molecule in the hypothalamus and pituitary, and show how it functions as an "on-off" switch for LIF-induced ACTH secretion. This was accomplished by regulating the LIF activity and allowing the cytokine to signal the pituitary gland to secrete ACTH.

"Pituitary SOCS-3 is thus shown to be the novel molecular connection for transducing the LIF cytokine-mediated brain signals to produce ACTH," Dr. Melmed stated.

An associate dean and professor of medicine at University of California-Los Angeles (UCLA), Dr. Melmed is a principal investigator funded by the National Institutes of Health. He has served as editor in chief for a number of scholarly publications, including Pituitary, Endocrine Updates and Endocrinology, and is widely published in scientific journals. He is also the pituitary editor for major endocrinology and internal medicine textbooks.

Dr. Melmed has received a number of honors and awards: Best Doctors in America (1994-1999); Pituitary Society Award, Contributions to Understanding Pituitary Disease (1997); McGill University, Neuro-Endocrinology Award (1995); and Royal Society of Medicine, Clinical Endocrinology Trust Medal (1994). A graduate of the University of Cape Town School of Medicine, South Africa, he is an elected member of the Association of American Physicians and the American Society of Clinical Investigation.

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