Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice.
In vitro, IL-6 is the main inducer of the human C-reactive protein (CRP) gene, and IL-1 and steroids can enhance this effect. However, in mice, IL-6 is necessary but not sufficient for induction of the human CRP transgene, and testosterone is required for its constitutive expression by males. To examine the relative contributions of testosterone and IL-6 in the regulation of CRP gene expression, we produced CRP-transgenic (CRPtg), IL-6-deficient (IL-6-/-) mice. Male CRPtg/IL-6-/- mice expressed CRP constitutively, but CRP levels were not increased after injection of LPS. However, acute-phase CRP levels were attained after injection of IL-6. In contrast, female CRPtg/IL-6-/- mice did not express CRP constitutively or after administration of LPS, IL-6, IL-1, or IL-6 plus IL-1. Like males, testosterone-treated CRPtg/IL-6-/- females expressed CRP constitutively, and their transgene responded to injection of IL-6. The endogenous acute-phase protein serum amyloid P (SAP) was expressed constitutively equally by male and female IL-6-/- mice, responded minimally to LPS, and did not respond to either IL-6 or IL-1 alone. Acute-phase levels of SAP were induced in IL-6-/- mice by injection of IL-6 together with IL-1 or LPS. We conclude that in vivo, both constitutive and IL-6-dependent acute-phase expression of the CRP transgene require testosterone. In contrast, testosterone is not required for expression of the SAP gene, which requires IL-1 plus IL-6 for acute-phase induction.
Szalai
A J
AJ
Department of Medicine, University of Alabama at Birmingham 35294, USA.
van Ginkel
F W
FW
Dalrymple
S A
SA
Murray
R
R
McGhee
J R
JR
Volanakis
J E
JE
D000367:Age Factors; D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000008:administration & dosage; D015850:Interleukin-6 / Q000008:administration & dosage / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000683:Serum Amyloid P-Component / Q000096:biosynthesis; D012737:Sex Factors; D013739:Testosterone / Q000008:administration & dosage / Q000502:physiology*; D019076:Transgenes / Q000276:immunology
D004338:Drug Combinations; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000683:Serum Amyloid P-Component; D013739:Testosterone; D002097:C-Reactive Protein