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Immune‐Induced Expression of Lipocalin‐2 in Brain Endothelial Cells: Relationship with Interleukin‐6, Cyclooxygenase‐2 and the Febrile Response
Author(s) -
Hamzic N.,
Blomqvist A.,
Nilsberth C.
Publication year - 2013
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12000
Subject(s) - cyclooxygenase , lipocalin , immune system , medicine , endocrinology , interleukin , inflammation , biology , immunology , chemistry , cytokine , enzyme , biochemistry
Interleukin (IL)‐6 is critical for the febrile response to peripheral immune challenge. However, the mechanism by which IL ‐6 enables fever is still unknown. To characterise the IL ‐6‐dependent fever generating pathway, we used microarray analysis to identify differentially expressed genes in the brain of lipopolysaccharide ( LPS )‐treated IL‐6 wild‐type and knockout mice. Mice lacking IL ‐6 displayed a two‐fold lower expression of the lipocalin‐2 gene ( lcn2 ), and this difference was confirmed by real‐time reverse transcriptase‐polymerase chain reaction. Conversely, the induction of lipocalin‐2 protein was observed in brain vascular cells following i.p. administration of recombinant IL ‐6, suggesting a direct relationship between IL ‐6 and lipocalin‐2. Immunohistochemical analysis also revealed that LPS ‐induced lipocalin‐2 is expressed by brain endothelial cells and is partly co‐localised with cyclooxygenase‐2 (Cox‐2), the rate‐limiting enzyme for the production of inflammatory induced prostaglandin E 2 ( PGE 2 ), which is the key mediator of fever. The direct role of lipocalin‐2 in fever was examined in LPS ‐challenged lipocalin‐2 knockout mice. In both male and female mice, normal fever responses were observed at near‐thermoneutral conditions (29–30 °C) but when recorded at normal room temperature (19–20 °C), the body temperature of lipocalin‐2 knockout female mice displayed an attenuated fever response compared to their wild‐type littermates. This difference was reflected in significantly attenuated m RNA expression of Cox‐2 in the brain of lipocalin‐2 knockout female mice, but not of male mice, following challenge with peripheral LPS . Our findings suggest that IL ‐6 influences the expression of lipocalin‐2, which in turn may be involved in the control of the formation of Cox‐2, and hence central PGE 2 ‐production. We have thus identified lipocalin‐2 as a new factor in the pathway of inflammatory IL ‐6 signalling. However, the effect of lipocalin‐2 on fever is small, being sex‐dependent and ambient temperature‐specific, and thus lipocalin‐2 cannot be considered as a major mediator of the IL ‐6‐dependent fever generating pathway.