Researchers at the University of California, San Diego (UCSD) School of Medicine have determined that a particular type of cellular stress called osmotic stress is of critical importance to cell growth and the body’s immune response against infection.
The findings may have implications for autoimmune disorders, transplant rejections, and potential cancer therapies.
Published in the online edition of the Proceedings of the National Academy of Sciences (PNAS) the week of July 5, 2004, the research in mice provided the first proof that a specific transcription factor, a gene that acts as an “on-off” switch, is essential for normal cell proliferation under conditions of osmotic stress and is also necessary for the body’s immune response to invading pathogens.
Osmotic stress occurs when the concentration of molecules in solution outside of the cell is different than that inside the cell. When this happens, water flows either into or out of the cell by osmosis, thereby altering the intracellular environment. Hyperosmotic stress causes water to diffuse out of the cell, resulting in cell shrinkage, which can lead to DNA and protein damage, cell cycle arrest, and ultimately cell death. Cells compensate or adapt to osmotic stress by activating an osmotic stress response pathway that is controlled by a gene called nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP). This NFAT5/TonEBP protein is the only known mammalian transcription factor that is activated by hyperosmotic stress.
Steffan N. Ho, M.D., Ph.D., a UCSD assistant professor of pathology and senior author of the paper in PNAS, noted that the findings bring to light new possibilities in the development of drugs to treat autoimmune diseases, transplant rejection and cancer.
“We are particularly excited about the implications of our findings to cancer cell biology,” Ho said. “The tissue microenvironment of tumors is unique because the unregulated growth of malignant cells does not allow for the normal development of blood and lymph vessels within the tumor, which could contribute to osmotic stress. If the growth of cancer cells in the body requires a means to adapt to osmotic stress, this stress response pathway would represent an exciting new target for the identification of anticancer drugs.”
In describing his team’s research, Ho said that it was previously thought that the kidney was the only tissue in the body that was subject to osmotic stress. The kidney controls how much water and salt is in our blood using a mechanism that results in very high levels of osmotic stress within certain areas of the kidney.
“As immunologists, we were at first rather puzzled when we found that a protein that was thought to help cells of the kidney adapt to osmotic stress was also expressed in tissues of the immune system,” Ho said. “There was no prior evidence that cells of the immune system or any other cell outside the kidney, for that matter, were exposed to significant osmotic stress in the body.”
One of the difficulties in studying the stresses that cells are exposed to within the body is the nearly impossible task of accurately recreating, in the laboratory, the complexities of a tissue with its unique microenvironment as it exists in vivo. To investigate osmotic stress, the Ho team generated mice that expressed a defective form of the NFAT5/TonEBP protein, and found that the mice had an impaired immune response; their cells were unable to grow when exposed to osmotic stress.
“We now think that the very process of cell proliferation within a tissue microenvironment exposes the cell to osmotic stress,” Ho said. “If the cell can’t adapt to that osmotic stress, it won’t be able to grow. The immune system is especially dependent on this osmotic stress response because in order to successfully overcome infection by viruses or bacteria, the cells of the immune system must proliferate very rapidly.”
The studies were supported by a grant from the National Institutes of Health, with shared core facility resources supported by a grant from the National Cancer Institute. In addition to Ho, the paper’s authors included first author William Y. Go, a student in the UCSD M.D./Ph.D. Medical Scientist Training Program; and co-authors Xuebin Liu, M.D., Ph.D., Michelle A. Roti, B.A., and Forrest Liu, M.D.