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The effect of TGF‐b1 on the IL2‐ and IL4‐ promoted T‐cell growth is differentially regulated by alpha‐2‐macroglobulin
Author(s) -
Koo Peter H.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1101-c
Subject(s) - interleukin 4 , transforming growth factor , cell growth , biology , t cell , growth factor , microbiology and biotechnology , chemistry , cytokine , immunology , receptor , biochemistry , immune system
TGF‐b1 is a pluripotent growth regulatory molecule, also known to inhibit the growth and differentiation of T cells. Alpha‐2‐macroglobulin (a2m) is a broadly specific proteinase inhibitor which binds to many cytokines; and in case of TGF, the binding neutralizes the suppressive activity of TGF‐b1 on keratinocyte growth and IL2‐activated killer cell differentiation. The objective of this study is to investigate the combined effect of a2m‐TGF on regulating T cell growth and differentiation. However, in our hands TGF‐b1 fails to suppress the growth of human T cells stimulated by anti‐CD3 and anti‐CD28. So we employed a cloned helper‐T (HT) which strictly depends on either IL2 or IL4 for growth and survival. TGF‐b1 dose‐dependently inhibits IL4‐promoted but stimulates IL2‐promoted HT‐proliferation. Either native a2m (N‐a2m) or monoamine‐activated a2m (MA‐a2m) itself has little or no effect on either IL2‐ or IL4‐ promoted HT growth. While higher doses of N‐a2m weakly neutralize the suppressive effect of TGF‐b1 on IL4‐promoted HT growth, a combination of N‐a2m and TGF‐b1 potently stimulates the growth of IL2‐treated HT cells. MA‐a2m dose‐dependently neutralizes the suppressive effect of TGF‐b1 on IL4‐treated HT cells, but enhances the stimulatory effect of TGF on IL2‐treated cells. The results suggest that (1) TGF‐b1 may down‐regulate Th‐2 differentiation but promote IL2‐dependent T cell growth, and N‐a2m which occurs naturally in diverse animal tissues appears to facilitate this TGF function; and (2) MA‐a2m, whose level in tissues is increased during inflammation, neutralizes TGF to minimize Th3/Tr differentiation but synergizes with TGF to facilitate T cell growth and Th1 differentiation.