UCSD researchers discover new role for immune-response enzyme

August 23, 2001

When viruses or bacteria assault the body, the immune system marshals its army of attack cells to ward off invaders. But sometimes, that arsenal of immune cells mistakenly ravages the body's own tissues, leading to a variety of autoimmune diseases such as rheumatoid arthritis, SLE (lupus) and multiple sclerosis.

Now, a team of scientists led by Michael Karin, Ph.D., UCSD professor of pharmacology and member of the UCSD Cancer Center, have discovered a new immunological pathway that opens a new avenue of research, with the potential for preventing autoimmune diseases and some lymphomas, without compromising the body's immune defenses.

Published in the August 24, 2001 issue of the journal Science, researchers from UCSD, Germany and Pennsylvania describe a previously unknown role for an enzyme call I-kappa-B kinase alpha (IKKa). Scientists have known that IKKa's cousin - an enzyme called IKK beta (IKKb) - is capable of acting without IKKa in initiating a molecular chain of events triggering the body's immune response. It was thought that IKKa's only role was in an unrelated function, the formation of the skin's outer layer.

With studies in test tubes and mice, researchers have now learned that IKKa also plays a role in the immune system, but acts independently of IKKb by taking a separate molecular pathway. IKKa is essential for development of B cells, one of the infection-fighting white cells that produce antibodies to invading pathogens, and for the formation of certain lymphoid organs and immune response genes.

Importantly, the scientists found that blocking the action of IKKa did not stop the IKKb-dependent immune response. It's this difference that offers a new research approach for autoimmune diseases. With additional work, researchers may find agents that can block only IKKa and over-expressed immune reactions that attack the body's own tissues, while protecting the immune system response with IKKb.

Karin noted that "if you can make specific inhibitors of IKKa that do not inhibit IKKb, we should be able to treat certain autoimmune disease without bringing on complete immunodeficiency. Right now, the treatment for autoimmune diseases is use of toxic drugs that knock out both B and T cells, necessary elements of the immune response."

Karin adds that the chemical chain of events initiated by IKKa is a molecular pathway also known to play a role in B cell lymphomas. By finding an inhibitor of IKKa, the scientists see potential for new treatments for this form of lymphoid cancer, as well as autoimmunity.

The new work in the Karin lab is a continuation of several years' investigation into the role of IKK, a multi-component protein complex identified in 1996 by the Karin team. Through that landmark work, and work done elsewhere, it was shown that IKK is responsible for controlling the body's inflammatory response, the first line of defense from microbial infections. In 1999, the Karin group found that IKK's beta subunit, IKKb, is essential for activation of the entire IKK complex by responding to chemical signal that trigger inflammation.

In response to infection and inflammation, IKKb attacks and degrades a molecule that holds captive an important family of proteins called NF-kB. Once freed, NF-kB generates the body's immune response. Although IKKa does not participate in this molecular chain of events, the research team discovered that IKKa controls the processing of one of the NF-kB proteins called NF-kB2, which is essential for development of B cells. In addition, they found that IKKa helps in the formation of germinal centers, areas within the lymph nodes where B cells rapidly divide and produce highly specific antibodies.

While both the beta and alpha subunits of IKK play a role in the immune response, the Karin team notes that the absence of IKKa can be compensated by IKKb in most cell types leading to normal NF-kB activation and defense against invading pathogens.
Authors of the Science paper in addition to Karin were first author Uwe Senftlebon, M.D., UCSD Department of Pharmacology and Clinic for Anesthesiology, University of Ulm, Germany; Yixue Cao, Ph.D., Florian R. Greten, M.D., Giuseppina Bonizzi, Ph.D., Yi Chen, Ph.D., and Yinling Hu, Ph.D., UCSD Department of Pharmacology; Gutlan Xiao, Ph.D., Abraham Fong, B.Sc., and Shao-Cong Sun, Ph.D, Pennsylvania State University College of Medicine; and Gertraud Krahn, M.D., Ph.D., UCSD Department of Pharmacology and University of Ulm, Germany Department of Dermatology.

The research was supported by postdoctoral fellowships from the Deutsche Forschungsgemeinschaft, the California Breast Cancer Research Project, Human Frontier Science Program, the Arthritis Foundation, and grants from the National Institutes of Health and the California Cancer Research Program.

University of California - San Diego

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