Liver and brain metallothionein regulation in transgenic mice overexpressing interleukin-6 and in mice carrying a null mutation in the interleukin-6 gene

Abstract

Interleukin-6 (IL-6) is a major cytokine which is an essential mediator of cellular communication not only of the immune system but also of other physiological systems. Results with mice carrying a null mutation in the IL-6 gene (IL-6-/-) demonstrate that IL-6 is an essential factor for normal liver metallothionein (MT) response not only to inflammatory stimuli (endotoxin, turpentine) but also to a basically psychogenic stress model-immobilization stress. This indicates that this cytokine is an important component of the physiological response of the organism to stress in addition to its expected role during an immunological challenge. In contrast to the liver, in the brain the IL-6 deficiency only affected significantly MT-I+II response to inflammatory stimuli. Results with transgenic mice expressing IL-6 under the regulatory control of the glial fibrillary acidic protein gene promoter (GFAP-IL6) indicate that the MT-I+II isoforms are strongly up-regulated by IL-6. The fold induction in different brain areas correlates with the associated inflammatory response, and is comparable to that of the acute-phase response gene EB22/5, suggesting that MT-I+II could be considered acute-phase proteins in the brain. MT-III expression in the GFAP-IL6 mice is elevated in some areas (e.g. cerebellum) and decreased in others (e.g. occipital cortex), while that in IL-6-/- mice is slightly affected in a brain area-specific manner.