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Articles in PresS, published online ahead of print March 7, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00746.2001
Submitted on December 17, 2001
Accepted on March 4, 2002
2-MACROGLOBULIN IN FEVER AND CYTOKINE RESPONSES INDUCED BY LIPOPOLYSACCHARIDE IN MICE
1 Institute of Physiology, National Academy of Sciences of Belarus, Minsk, Belarus
2 Lovelace Respiratory Research Institute, Albuquerque, NM, USA
3 Department of Human Genetics, Experimental Genetics Group, K.U.Leuven-Campus Gasthuisberg, Leuven, Belgium
4 Department of Physiology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: a.gourine{at}rfc.ucl.ac.uk.
2-Macroglobulin (2M) is not only a proteinase inhibitor in mammals, but also a specific cytokine carrier that binds pro- and antiinflammatory cytokines implicated in fever, including interleukin (IL)-1ß, IL-6, and tumour necrosis factor- (TNF). To define the role of 2M in regulation of febrile and cytokine responses wild-type mice and mice deficient in 2M (2M -/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1ß, IL-6 and TNF and hepatic TNF- mRNA level during fever in 2M -/- mice were compared to those in wild-type control mice. The 2M -/- mice developed a short-term markedly attenuated (ANOVA, p<0.05) fever in response to LPS (2.5 mg/kg, I.P.) compared to the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-, but not IL-1ß or IL-6, was significantly lower (by 58%) in the 2M -/- mice compared with their wild-type controls (ANOVA, p<0.05). There was no difference in hepatic TNF mRNA levels between 2M-/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that (i) 2M is important for the normal development of LPS-induced fever; (ii) a putative mechanism of 2M involvement in fever is through the inhibition of TNF- clearance. These findings indicate a novel physiological role for 2M.
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