Role of alpha(2)-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice.
Alpha(2)-macroglobulin (alpha(2)M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). To define the role of alpha(2)M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in alpha(2)M (alpha(2)M -/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1beta, IL-6, and TNF-alpha and hepatic TNF-alpha mRNA level during fever in alpha(2)M -/- mice were compared with those in wild-type control mice. The alpha(2)M -/- mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-alpha, but not IL-1beta or IL-6, was significantly lower (by 58%) in the alpha(2)M -/- mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-alpha mRNA levels between alpha(2)M -/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) alpha(2)M is important for the normal development of LPS-induced fever and 2) a putative mechanism of alpha(2)M involvement in fever is through the inhibition of TNF-alpha clearance. These findings indicate a novel physiological role for alpha(2)M.
Gourine
Alexander V
AV
Institute of Physiology, National Academy of Sciences of Belarus, Minsk 220725, Belarus. a.gourine@rfc.ucl.ac.uk
Gourine
Valery N
VN
Tesfaigzi
Yohannes
Y
Caluwaerts
Nathalie
N
Van Leuven
Fred
F
Kluger
Matthew J
MJ
D000510:Alpha-Globulins / Q000502:physiology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced* / Q000503:physiopathology*; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012997:Solvents; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D014425:Turpentine
D000510:Alpha-Globulins; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012997:Solvents; D014409:Tumor Necrosis Factor-alpha; C025500:alpha(2)-microglobulin; D014425:Turpentine