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Experimental Genetics Group

Bolleke Abstract   Pijltje
Role of alpha(2)-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice.

Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R218-26.

Gourine AV1, Gourine VN1, Tesfaigzi Y2, Caluwaerts N3, Van Leuven F3, Kluger MJ4.

1Institute of Physiology, National Academy of Sciences of Belarus, Minsk, Belarus.
2Lovelace Respiratory Research Institute, Albuquerque, New Mexicao.
3Experimental Genetics Gorup, Department of Human Genetics, K.U.Leuven, Leuven, Belgium.
4Medical College of Georgia, Augusta, Georgia.

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.

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