A factor in immune cells regulates human semen and seems to determine whether a man will be fertile, according to a new study.

Dr. Yousef Al-Abed, PhD, and colleagues at The Feinstein Institute for Medical Research isolated an immune substance called macrophage migration inhibitory factor (MIF) in semen samples from infertile and reproductively healthy men. MIF is crucial to helping human sperm mature, which is a necessity for its union with an egg. This finding could lead to an effective test for determining fertility.

This One is Just Right

In the study, published the journal Molecular Medicine, semen samples were collected from men three to five days after a period of sexual abstinence. The scientists analyzing levels of MIF were not told whether the sample came from one of the 68 men who had fertility problems or from the 27 healthy controls. The findings have a Goldilocks kind of quality: Those with infertility problems had MIF levels that were either too high or too low. Those who had no problems conceiving had levels that were just right.

When scientists added macrophage migration inhibitory factor into lab dishes containing healthy sperm, the MIF decreased the count and impaired their motility. The fact that MIF may, in fact have a role in infertility, leads Dr. Al-Abed and his colleagues to speculate whether it might work as a form of male contraception.

The Immune System and MIF

MIF plays a key role in the immune system. MIF was identified over 40 years ago, but only recently have scientists realized its role as a pro-inflammatory substance. MIF has now been linked to many autoimmune and inflammatory diseases - such as diabetes and sepsis - and Dr. Al-Abed, who is an organic chemist by training, has been attempting to identify and design small molecules which would block MIF activity.

The Feinstein researchers recently identified a critical area on the MIF protein surface that is crucial for the inflammatory response. Such a substance designed to target this area could be used to treat a variety of conditions, including septic shock, sepsis, rheumatoid arthritis and diabetes.

The team designed a specific inhibitor called ISO-1 to fit into this pro-inflammatory site. In an animal model of sepsis, ISO-1 abolishes MIF’s potent inflammatory abilities and the animals respond dramatically. They lived through the once-fatal sepsis.

In patients in the throes of sepsis - an over-reactive and potentially fatal immune response to a bacterial infection - MIF concentrations are 10 to 20 times higher than normal. If MIF goes down, the chance that patients will survive sepsis is increased dramatically. “The idea is to suppress inflammation so that cells stop producing MIF,” said Dr. Al-Abed.

Every year, 215,000 Americans die of sepsis, a systemic inflammatory reaction to infection. Another 500,000 survive the infection, and scientists are still trying to figure out why these patients survive and others don’t. There are no treatments for this massive all-out war on the body.

Those who survive often face serious cardiovascular problems. Scientists examining cardiac function during sepsis have identified macrophage migration inhibitory factor (MIF) as a key factor in heart damage. And antibodies targeted to MIF, so-called anti-MIF antibodies, significantly improves cardiac performance during septic shock. Clearly, the possible uses of MIF in medical treatment deserves a closer look.

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