Abstract
Human alpha 2-macroglobulin (alpha 2M), which irreversibly entraps proteinases through a drastic conformational change, has also been reported to bind various cytokines. The meaning of cytokine binding to native and/or transformed alpha 2M molecules is, however, not understood. In an attempt to elucidate this question, we have studied the interaction of radioiodinated recombinant human interleukin-2 (125I-rhIL-2) with native and chymotrypsin (alpha 2M-C)- or methylamine-transformed (alpha 2M-MA) alpha 2M. Our results show that native and alpha 2M-MA are able to bind 125I-rhIL-2, with binding occurring only with the latter in a covalent manner, whereas the labeled cytokine is proteolyzed when incubated with alpha 2M-entrapped chymotrypsin. The degradation of uncomplexed 125I-rhIL-2 has also been observed in the presence of trypsin, whereas 125I-rhIL-2 bound to alpha 2M-MA is protected. Moreover, the proliferative activity of this cytokine on responsive cells is still maintained either with native alpha 2M- or alpha 2M-MA-complexed rhIL-2 in comparison with that observed with the cytokine alone. Our results, which lead us to consider alpha 2M molecules as IL-2-binding proteins, emphasize the possible role of these molecules as immune response regulators.
Highlights
§ Recipient of two fellowships, from the 1nstitut Gustave-Roussy (CRC number 92-11) and from La Fondation Jean Dausset (Association des Amis Sciences, 16 Rue Mazarine, Paris, France), successively
A similar conformational change in a 2M is obtained after nucleophile hydrolysis of these thiol ester bonds by primary amines, e.g. methylamine, in the absence of proteolytic cleavage
The present paper reports the first demonstration by polyacrylamide gel electrophoresis (PAGE) analysis of biochemical interactions between 1251-rhiL-2 and different forms of a 2M
Summary
Evidence for the Binding of a Biologically Active Interleukin-2 to Human a2-Macroglobulin*. IIGroupe Cytokines et Immunite Antitumorale, CJF 94-11, Institut National de la Sante et de la Recherche Medicate, Institut Gustave-Roussy, Rue Camille-Desmoulins, F-94805 Villejuif Cedex, France. Human a2-macroglobulin (a2 M), which irreversibly entraps proteinase& through a drastic conformational change, has been reported to bind various cytokines. In an attempt to elucidate this question, we have studied e the interaction of radioiodinated recombinant human interleukin-2 261-rhiL-2) with native and chymotrypsin (a2 M-C)- or methylamine-transformed (a~-MA) a 2M. The two existing Fforms cannot be distinguished by PAGE but are differentiated by electron microscopy (EM) [6] As soon as it was identified as a foremost plasma-binding protein for several growth factors and interleukins The present paper reports the first demonstration by PAGE analysis of biochemical interactions between 1251-rhiL-2 and different forms of a 2M
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