Expression of a biologically active recombinant mouse IL-1 receptor antagonist and its use in vivo to modulate aspects of the acute phase response.
Recombinant mouse IL-1receptor antagonist protein (rmIL-1ra) was expressed in Escherichia coli. In vivo administration of rmIL-1ra, in a casein-induced murine model of acute inflammation, completely abolished the hepatic induction of the mRNAs specifying serum amyloid A1 (A-SAA1) and A-SAA2 for up to 12 h, indicating that hepatic A-SAA mRNA synthesis is totally IL-1 driven. A-SAA protein, however, was present in the serum of rmIL-1ra-treated casein-stimulated mice (although at lower levels than in untreated casein-stimulated mice) at 12 h indicating that extrahepatic A-SAA synthesis is driven in part by factors acting independently of IL-1. Hepatic mRNA levels of the other mouse acute phase reactants (APRs), serum amyloid P component, C-reactive protein, alpha1-acid glycoprotein, and C3 were also induced with casein after 12 h, as were serum protein levels of SAP and C3. These inductions were only partially inhibited by rmIL-1ra, indicating that hepatic expression of the latter APRs (unlike that of A-SAA) is driven partly by IL-1 and partly by factors acting independently of IL-1. Hepatic mRNA levels of the negative APRs apolipoprotein A-I and serum albumin were down-regulated 12 h after casein stimulation. rmIL-1ra partially restored serum albumin mRNA levels but not apo A-I mRNA levels, indicating differential regulation of these negative APRs. The rmIL-1ra will be useful in studies of IL-1-mediated gene regulation in murine models of inflammation.
Grehan
S
S
Department of Genetics and Biotechnology Institute, Trinity College, Dublin, Ireland.
Uhlar
C M
CM
Sim
R B
RB
Herbert
J
J
Whitehead
A S
AS
D000210:Acute-Phase Reaction / Q000188:drug therapy / Q000276:immunology*; D000682:Amyloid / Q000032:analysis; D000818:Animals; D002460:Cell Line; D004926:Escherichia coli; D053590:Interleukin 1 Receptor Antagonist Protein; D008099:Liver / Q000187:drug effects / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D000682:Amyloid; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins