High plasma levels of MIF are often correlated with increased inflammation. A key aspect to consider, regarding the microgram quantities of MIF residing in red blood cells, is the implications of cell lysis in disease or injury. Red blood cell lysis can occur following injury, which would release high concentrations of enzymatically and chemotactically active MIF. This immediate release of high levels of MIF may actually play a role in the early stages of the immune response to injury. There is considerable literature on the protective effects of MIF and a recent paper on an animal model of ischemia reperfusion injury after myocardial infarction demonstrated that MIF exerts both pro-inflammatory effects and protective effects in cardiomyocytes61.
It is important to note that the data enclosed in this chapter was collected using blood from healthy volunteers, and as such, analysis of blood isolated from specific disease cohorts in the
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future would be of value. MIF is frequently cited as being present at increased concentrations in the plasma of diseased cohorts when compared to the healthy controls10-12. It is not
unreasonable, therefore, to hypothesise that the concentration of MIF in, or being released by, red blood cells may also differ in these groups. Further research in this area should seek to determine if there is any correlation between red blood cell associated MIF and the initiation, progression, or the protection against inflammatory disease.
MIF in red blood cells is likely present for a number of reasons. It is part of the mechanism by which the red blood cell manages oxidative stress, and it is able to exert its pro-inflammatory and protective functions upon lysis. Like MIF, red blood cells too are playing multiple roles. Whilst their primary role is in a gas transport and exchange, they are also likely to be involved in the immune response. Further investigation into this alternative role for red blood cells will be outlined in Chapter 4.
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ONCLUSION
The results of this chapter demonstrate that in vivo haemolysis would result in the release of high concentrations of active MIF. Unless this excess MIF is modulated or deactivated in other ways, this released MIF would exert its pro-inflammatory signalling activity on surrounding cells. MIF has been described as an important factor in a wide variety of diseases and a review of the literature presents a rich tapestry of its interactions in many cell types, including both pro-inflammatory and protective effects in the same injury model. The identification and quantification of this cytokine in its active form in the most abundant cell type in the body (red blood cells) is likely to contribute to the understanding of a number of these MIF associated conditions. MIF is present in whole blood in microgram quantities per millilitre, however, during normal function, over 90 % is sequestered in the red blood cell cytosol. The release of MIF in microgram per millilitre concentrations after injury suggests that highly effective mechanisms are present to suppress its chemokine activity. Given the literature on the protective functions of MIF, an alternative hypothesis is that extracellular MIF has a cell and tissue protective function that may be its primary role after acute injury62.
This discovery could have implications on conditions such as haemolytic anaemia, wound healing and clot formation, sepsis, and adverse events following red blood cell transfusions. More research is required to elucidate the involvement of red blood cell derived MIF in a variety of processes, but this discovery may change the way that disease is researched, including its progression and the involvement of the immune system. Just as ‘junk DNA’ was discovered to be anything but ‘junk’, so too are red blood more active than was once thought. Subsequent chapters in this thesis investigate the presence of other cytokines and growth factors in red blood cells that may be working in concert with MIF to communicate with the immune system.
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