Oxidized α2-Macroglobulin (α2M) Differentially Regulates Receptor Binding by Cytokines/Growth Factors: Implications for Tissue Injury and Repair Mechanisms in Inflammation

Abstract

Abstract α2M binds specifically to TNF-α, IL-1β, IL-2, IL-6, IL-8, basic fibroblast growth factor (bFGF), β-nerve growth factor (β-NGF), platelet-derived growth factor (PDGF), and TGF-β. Since many of these cytokines are released along with neutrophil-derived oxidants during acute inflammation, we hypothesize that oxidation alters the ability of α2M to bind to these cytokines, resulting in differentially regulated cytokine functions. Using hypochlorite, a neutrophil-derived oxidant, we show that oxidized α2M exhibits increased binding to TNF-α, IL-2, and IL-6 and decreased binding to β-NGF, PDGF-BB, TGF-β1, and TGF-β2. Hypochlorite oxidation of methylamine-treated α2M (α2M*), an analogue of the proteinase/α2M complex, also results in decreased binding to bFGF, β-NGF, PDGF-BB, TGF-β1, and TGF-β2. Concomitantly, we observed decreased ability to inhibit TGF-β binding and regulation of cells by oxidized α2M and α2M*. We then isolated α2M from human rheumatoid arthritis synovial fluid and showed that the protein is extensively oxidized and has significantly decreased ability to bind to TGF-β compared with α2M 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-α, IL-2, and IL-6, while up-regulating the development of tissue repair processes by releasing bFGF, β-NGF, PDGF, and TGF-β from binding to α2M.