Download Expression of Angiotensin-converting Enzyme Changes Major

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J Biol Chem. 2008 Apr 11;283(15):9957-65. Epub 2008 Feb 5.
Expression of Angiotensin-converting Enzyme Changes Major Histocompatibility Complex Class
I Peptide Presentation by Modifying C Termini of Peptide Precursors.
Shen XZ, Lukacher AE, Billet S, Williams IR, Bernstein KE.
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322.
We recently reported a mouse model called ACE 10/10 in which macrophages overexpress the
carboxypeptidase angiotensin-converting enzyme (ACE). These mice have an enhanced inflammatory
response to tumors that markedly inhibits tumor growth. Here, we show that ACE modifies the C termini
of peptides for presentation by major histocompatibility complex (MHC) class I molecules. The
peptide-processing activity of ACE applies to antigens from either the extracellular environment
(cross-presentation) or antigens produced endogenously. Consistent with its role in MHC class I antigen
processing, ACE localizes to the endoplasmic reticulum. ACE overexpression does not appear to change
the overall supply of peptides available to MHC class I molecules. The immunization of wild type mice
previously given ACE 10/10 macrophages enhances the efficiency of antigen-specific CD8(+) T cell
priming. These data reveal that ACE is a dynamic participant in fashioning the peptide repertoire for MHC
class I molecules by modifying the C termini of peptide precursors. Manipulation of peptidase expression
by antigen-presenting cells may ultimately prove a useful strategy to enhance the immune response.
PMID: 18252713 [PubMed - in process]
原文
Expression of Angiotensin-converting Enzyme Changes Major Histocompatibility Complex Class
I Peptide Presentation by Modifying C Termini of Peptide Precursors.
By increasing production of a blood pressure-regulating enzyme in mice, researchers have found they
can enhance the mouse immune system's ability to sense tumor growth.
When scientists at Emory University School of Medicine engineered mice that make more
angiotensin-converting enzyme in white blood cells called macrophages, the mice could more effectively
limit the growth of injected tumors.
The enzyme works by "trimming" small bits of protein that originate from the tumors, allowing the immune
system to identify the tumors and mount a response more efficiently.
The results are published online in the Journal of Biological Chemistry (JBC).
Senior author Kenneth Bernstein, MD, Emory distinguished service professor of pathology and laboratory
medicine, says his group's findings suggest a strategy for amplifying immune system function in humans.
"We think we've discovered a means of tweaking the immune response by modifying the process of
antigen presentation," Dr. Bernstein says.
In the clinic, doctors might be able to enhance a cancer patient's ability to resist a tumor by removing his
or her white blood cells, boosting their production of angiotensin-converting enzyme, and re-infusing
them, he says.
Antigen presentation refers to how proteins from within the body are constantly recycled and chewed up
into small bits called peptides, which appear on the surfaces of cells. While the immune system generally
ignores peptides from proteins in the body, it can respond to the peptides from foreign invaders.
Angiotensin-converting enzyme, or ACE, plays a critical role in controlling blood pressure and is the
target of common medications. The hormone angiotensin (a peptide) constricts blood vessels, increases
the brain's perception of thirst and indirectly causes the kidneys to retain sodium, thus limiting its
production can reduce blood pressure.
ACE acts chemically by removing amino acids, the building blocks of proteins, from one end of a larger
protein. In the body, ACE converts an inactive form of angiotensin into an active form by clipping off two
amino acids.
But angiotensin is not ACE's only target. In previous studies, Bernstein and his co-workers found that
manipulating its activity also affects processes such as fertility and the generation of red blood cells in the
bone marrow.
To dissect out ACE's role in the immune system, they created mice with a genetic alteration in the ACE
gene, forcing the gene to be turned on only in macrophages.
Macrophages are especially good at displaying peptides on their surfaces to other white blood cells
called T cells so that the T cells are stimulated to grow. The T cells in turn kill virally infected cells.
Depending on the situation, they can sometimes kill tumor cells as well.
When injected with several types of melanoma or lymphoma, the altered mice developed smaller tumors
than normal mice. The tumors they did have contained more white blood cells attacking the cancerous
cells.
In the JBC paper, the researchers show that ACE boosts cells' ability to display some foreign peptides,
increasing their ability to stimulate T cells by several-fold.
Bernstein cautions that normally, macrophages make little ACE, so its effects must be seen as artificial.
He notes that ACE inhibitors such as enalapril and lisinopril are taken by millions of people with high
blood pressure and have not been reported to weaken the immune system.
However, cells similar to macrophages have been shown to produce ACE in response to pathogens such
as sarcoid or leprosy, he says.
---------------------------Article adapted by Medical News Today from original press release.
----------------------------
The first author of the paper is postdoctoral fellow Xiao Shen, PhD, with contributions from Aron Lukacher
MD, PhD and Ifor Williams MD, PhD, both Emory associate professors of pathology and laboratory
medicine.
The research was supported by the National Institutes of Health and the American Heart Association.
Source: Holly Korschun
Emory University