Genetics and Biochemistry Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892-1587
Address correspondence and requests for reprints to: Jacob Robbins, M.D., Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 6C 201A, Bethesda, Maryland 20892-1587.
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Introduction |
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Other members of the SERPIN family, while sharing many molecular
properties, lack protease inhibitory activity. Among them are the
abundant egg protein, ovalbumin, and the much less abundant plasma
proteins TBG and its sister hormone-binding protein, CBG,
corticosteroid binding globulin (5). A molecular property
that these proteins share is the structural response to limited
proteolysis, and in the case of the hormone transporters, the obvious
question is whether the change in structure can affect hormone binding.
Pemberton et al. (6) found that exposure to
elastase increased the thermal stability of both TBG and CBG, but
affinity for the respective hormone was decreased only in the case of
CBG. Modeling of the molecular structure of the cleaved TBG, based on
its homology with -1 antitrypsin (7, 8), then led to a
detailed definition of the T4 binding site, an achievement
that had not been possible by conventional methods.
In this issue of JCEM, Jirasakuldech et al. (9) now present convincing evidence that exposure of TBG to pancreatic elastase or to activated polymorphonuclear leukocytes does, in fact, bring about a major decrease in its affinity for T4. A similar result was reported earlier in abstracts published by the same group (10) and from two other laboratories (11, 12) using three different methods: dialysis, resin uptake, and ANS (analinonaphthalene sulfonic acid) competition. Schusslers group also demonstrated that the limited proteolysis was more than simply an in vitro phenomenon. By studying patients afflicted by bacterial sepsis, they were also able to show the presence of the cleaved TBG molecule in serum by virtue of its altered size but persistent binding to anti-TBG immunoglobulin (9).
In the case of CBG, it is easy to imagine that release of cortisol at the site of an inflammatory process might have an important pathophysiological role. Hammond et al. (13, 14) showed that leukocytes activated by inflammation caused hormone release from CBG and that this event takes place at the leukocyte plasma membrane. Cortisol of course has known anti-inflammatory action. The potential role of increased T4 or T3 release from TBG is less obvious. Over 30 yr ago, Klebanoff (15) explored the antibacterial effect of iodine in a myeloperoxidase system. Although iodide was 200 times more effective than chloride, the much larger available concentration of chloride made the role of iodide less attractive. Subsequent experiments by Klebanoff and Green (16), however, demonstrated that activated leukocytes rapidly degrade T4 and T3 and greatly increase the iodide concentration within the cell. Others demonstrated an accelerated disappearance of T4 and T3 from plasma in pneumococcal infection in man (17) and in monkeys (18). It is tempting to postulate, as Jirasakuldech et al. (9) have done, that localized release of T4 from TBG by limited proteolysis might play a role in pathological, and even in physiological, processes. Very rough calculations suggest that release in a few hours of about half of the bound T4 in a relatively small volume of infected tissue might, if leukocytes can deiodinate T4 quickly, provide enough iodide and iodine for significant bactericidal activity. An important corollary is that this release would take place at specific anatomical sites in response to some initiating event, such as an infection or an inflammatory response to trauma. (See Ref. 19 in their report.) The authors also raise the interesting possibility that this phenomenon may explain the increased free to bound T4 ratio and other abnormalities seen in nonthyroidal illness, and the rapid fall in serum T4 that may occur during acute inflammation [their Refs. 26 and 20, and work from their own laboratory (Ref. 11 , still in press)].
A side issue in their experiments is the finding of a large band of protein with an apparent molecular mass of 27 kDa in immunoblotting of SDS-PAGE-separated proteins from both normal and sepsis serum. Their interpretation that this probably is due to reaction of an impure anti-TBG antiserum with apolipoprotein A-1 should alert readers to the need for more pure antisera when performing immunoassay of TBG in serum. A significant achievement in their experiments with sepsis serum, however, is the demonstration of a sizable amount of cleaved TBG with mass 4950 kDa. Because the cleaved remnants of other SERPINs have been found to have new and unexpected biological activities (their Refs. 6, 24, and 25)witness the antiangiogenic and tumor suppressive activity recently demonstrated for cleaved antithrombin III (19)this raises the tantalizing possibility that TBG may also possess hidden biological effects.
Further speculation on potential pathophysiological effects of limited TBG proteolysis has been presented by Schussler in a recent review (20). These interesting experiments and ideas should serve to rescue TBG from the doldrums in the foreseeable future.
Received September 11, 2000.
Accepted September 13, 2000.
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References |
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