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2-Macroglobulin (2M) Differentially Regulates Receptor Binding by Cytokines/Growth Factors: Implications for Tissue Injury and Repair Mechanisms in Inflammation1
Departments of
*
Pathology and
Medicine, Division of Rheumatology, Duke University Medical Center, Durham, NC 27710
2M binds specifically to TNF-, IL-1ß,
IL-2, IL-6, IL-8, basic fibroblast growth factor (bFGF), ß-nerve
growth factor (ß-NGF), platelet-derived growth factor (PDGF), and
TGF-ß. Since many of these cytokines are released along with
neutrophil-derived oxidants during acute inflammation, we hypothesize
that oxidation alters the ability of 2M to bind to these
cytokines, resulting in differentially regulated cytokine functions.
Using hypochlorite, a neutrophil-derived oxidant, we show that oxidized
2M exhibits increased binding to TNF-, IL-2, and IL-6
and decreased binding to ß-NGF, PDGF-BB, TGF-ß1, and TGF-ß2.
Hypochlorite oxidation of methylamine-treated 2M
(2M*), an analogue of the proteinase/2M
complex, also results in decreased binding to bFGF, ß-NGF, PDGF-BB,
TGF-ß1, and TGF-ß2. Concomitantly, we observed decreased ability to
inhibit TGF-ß binding and regulation of cells by oxidized
2M and 2M*. We then isolated
2M from human rheumatoid arthritis synovial fluid and
showed that the protein is extensively oxidized and has significantly
decreased ability to bind to TGF-ß compared with 2M
derived from plasma and osteoarthritis synovial fluid. We, therefore,
propose that oxidation serves as a switch mechanism that down-regulates
the progression of acute inflammation by sequestering TNF-, IL-2,
and IL-6, while up-regulating the development of tissue repair
processes by releasing bFGF, ß-NGF, PDGF, and TGF-ß from binding to
2M.
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