Zinc helps balance immune response

Friday, February 15, 2013. On February 7, the journal Cell Reports published the findings of Daren Knoell and colleagues at Ohio State University (OSU) of an immune-regulating effect for the mineral zinc in sepsis, a systemic response to infection that frequently causes death in intensive care unit (ICU) patients. Zinc deficiency is estimated to occur in 40 percent of older individuals: a population that is also more likely to be admitted to the ICU.

In previous research conducted by Dr Knoell's laboratory, mice provided with zinc deficient diets exhibited high levels of inflammation in response to sepsis in comparison with mice given normal diets. However, deficient mice supplemented with zinc had less inflammation than their unsupplemented counterparts.

"The immune system has to work under very strict balance, and this is a classic example of where more is not always better," stated Dr Knoell, who is a professor of pharmacy and internal medicine at OSU. "We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage."

The current research involved human immune cells known as monocytes. In the immune response, a protein known as nuclear factor kappa-beta (NF-kB) is activated and enters the cell nucleus. Dr Knoell and colleagues report that this action triggers the expression of a gene that produces ZIP8, a zinc transporter, which locates to the cell wall where it facilities the entry of zinc from the blood. Zinc then binds another protein in the NF-kB pathway known as IKKB, which halts further activity, thereby preventing excessive inflammation such as occurs during sepsis. Experimentation involving zinc-deficient mice with sepsis confirmed the correlation between increased inflammation and reduced control of IKKB signaling. "The benefit to health is explicit: zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation," Dr Knoell explained. "There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region."

"We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis," he remarked. "Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection – if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so."

"We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would," he continued. "Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too."

"We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection," he concluded. "There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?"

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