TY - JOUR
T1 - A lymphokine regulates expression of alpha-1-proteinase inhibitor in human monocytes and macrophages
AU - Takemura, S.
AU - Rossing, T. H.
AU - Perlmutter, D. H.
PY - 1986
Y1 - 1986
N2 - Biosynthesis and secretion of alpha-1-proteinase inhibitor (α1PI) has been demonstrated in primary cultures of human mononuclear phagocytes, making it possible to study regulation of α1PI in normal (PiMM) and homozygous-deficient (PiZZ) individuals. In this study, expression of α1PI by blood monocytes, bronchoalveolar, and breast milk macrophages decreased during 1 wk in culture whereas expression of other secreted proteins increased. The addition of crude supernatants from mitogen-stimulated peripheral blood mononuclear cells to confluent monolayers of mononuclear phagocytes after 1 wk in culture resulted in a 2- to 2.5-fold increase in α1PI expression. The increase in α1PI expression was dose- and time-dependent, and involved a mechanism acting at a pretranslational level as shown by an increase in specific messenger RNA content corresponding to the increase in synthesis and secretion of α1PI. Although α1PI was expressed in native form and in forms complexed with serine protease by monocytes early in culture, it was expressed in its native form alone when monocytes were incubated with the lymphokine after 1 wk in culture. The regulating factor had the characteristics of a polypeptide and was derived from T lymphocytes, but it was not interferon-alpha, -beta, -gamma, or interleukin 2. This lymphokine also stimulated synthesis of α1PI in monocytes of homozygous-deficient PiZZ individuals, but had minimal effect on secretion, thereby increasing the intracellular accumulation of the inhibitor and exaggerating the defect in secretion of α1PI in these individuals. Regulation of mononuclear phagocyte α1PI expression by a lymphokine provides a model for further analysis of the effect of enhanced synthesis on a defect in posttranslational processing/secretion and for analysis of differential regulation of protease and inhibitor expressed in the same cells.
AB - Biosynthesis and secretion of alpha-1-proteinase inhibitor (α1PI) has been demonstrated in primary cultures of human mononuclear phagocytes, making it possible to study regulation of α1PI in normal (PiMM) and homozygous-deficient (PiZZ) individuals. In this study, expression of α1PI by blood monocytes, bronchoalveolar, and breast milk macrophages decreased during 1 wk in culture whereas expression of other secreted proteins increased. The addition of crude supernatants from mitogen-stimulated peripheral blood mononuclear cells to confluent monolayers of mononuclear phagocytes after 1 wk in culture resulted in a 2- to 2.5-fold increase in α1PI expression. The increase in α1PI expression was dose- and time-dependent, and involved a mechanism acting at a pretranslational level as shown by an increase in specific messenger RNA content corresponding to the increase in synthesis and secretion of α1PI. Although α1PI was expressed in native form and in forms complexed with serine protease by monocytes early in culture, it was expressed in its native form alone when monocytes were incubated with the lymphokine after 1 wk in culture. The regulating factor had the characteristics of a polypeptide and was derived from T lymphocytes, but it was not interferon-alpha, -beta, -gamma, or interleukin 2. This lymphokine also stimulated synthesis of α1PI in monocytes of homozygous-deficient PiZZ individuals, but had minimal effect on secretion, thereby increasing the intracellular accumulation of the inhibitor and exaggerating the defect in secretion of α1PI in these individuals. Regulation of mononuclear phagocyte α1PI expression by a lymphokine provides a model for further analysis of the effect of enhanced synthesis on a defect in posttranslational processing/secretion and for analysis of differential regulation of protease and inhibitor expressed in the same cells.
UR - http://www.scopus.com/inward/record.url?scp=0022550810&partnerID=8YFLogxK
U2 - 10.1172/JCI112423
DO - 10.1172/JCI112423
M3 - Article
C2 - 3485658
AN - SCOPUS:0022550810
SN - 0021-9738
VL - 77
SP - 1207
EP - 1213
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -