The cell culture study by a research team from The Children's Hospital of Philadelphia and the University of Pennsylvania appears in the Proceedings of the National Academy of Sciences, published online on May 4.
The team, led by Steven D. Douglas, M.D., chief of the Section of Immunology at The Children's Hospital of Philadelphia, analyzed neurokinin-1 receptors found on the surfaces of monocytes, immune cells that develop into macrophages. The neurokinin-1 receptors (NK-1R) are docking sites for substance P, a well-known neurotransmitter that plays important roles in both immune function and the nervous system.
In the current study, the Douglas team investigated two forms of NK-1R in a human monocyte/macrophage cell line. One was a full-length receptor, the other a shortened version with fewer amino acids. When the researchers added substance P to cell cultures with the receptors, both responded with an increase in calcium ions, but used distinct signaling pathways.
The truncated NK-IR did not respond directly to substance P, but worked through another signaling molecule, the chemokine RANTES, to increase the calcium flow. The RANTES molecule is important because it binds to another cell receptor, CCR5, which is crucial in allowing common strains of HIV (R5 strains) to infect immune cells.
Significantly, when the investigators added the drug aprepitant, which binds to NK-1R, to their cell cultures, it inhibited signaling from both the full-length and short form of the receptors.
Although the current study was not focused on HIV infection, it directly relates to broader interests of Dr. Douglas' laboratory. He currently leads a four-year program project grant from the National Institute of Mental Health, entitled, "Neurokinin-1R (Substance P Receptor) Antagonists for HIV Therapy." One project within that grant will conduct a phase 1 (safety) trial of aprepitant in adults with HIV infection. Currently used as an anti-nausea medication, aprepitant, which has the trade name Emend, might also block HIV infection.
Because macrophages are a reservoir for HIV, a strategy that denies the virus entry into those immune cells may be important in combating HIV infection. Dr. Douglas showed in 2001 that another NK-1R antagonist blocked HIV replication within macrophages in cell culture. The hope is that aprepitant may show a similar protective effect in patients.
"We postulate that blocking NK-1R may send signals to turn off the CCR5 receptor for HIV, closing the door to the virus," said Dr. Douglas. "Underlying the signaling mechanisms are the questions, 'how does the immune system talk to the nervous system?' and 'how does the nervous system talk back?' Substance P is a link between both systems, and this study increases our understanding of those underlying questions."
The National Institutes of Health supported this research. Dr. Douglas' co-authors, all from The Children's Hospital of Philadelphia and the University of Pennsylvania, are Jian-Ping Lai, M.D., Wen-Zhe Ho, M. Sc., Laurie E. Kilpatrick, Ph.D., Xiao Wang, M.S., Florin Tuluc, M.D., Ph.D., and Helen M. Korchak, Ph.D.
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
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