Coordinated regulation of ceruloplasmin and metallothionein mRNA by interleukin‐1 and copper in HepG2 cells

Abstract

During the acute phase response, cytokines induce hepatic metallothionein and ceruloplasmin synthesis and the uptake of metals. We have investigated how copper and cytokines may interact in controlling ceruloplasmin (CP) and metallothionein mRNA in liver cells. We found that IL-1K K, IL-1L L and IL-6 increased both metallothionein-1 (MT-1) and metallothionein-2 (MT-2) mRNA in HepG2 cells. The time and pattern of induction was different, both IL-1K K and IL-1L L inducing two peaks of MT-1 and MT-2, with that of MT-2 being much larger. IL-6 induced only low levels of both MT-1 and MT-2 mRNA. CP mRNA was also increased after 16 h by IL-1L L, whereas IL-1K K induced two CP peaks at 8 and 20 h, while IL-6 had little effect. Copper administration gave rise to substantially increased MT-1 mRNA, a slightly lower increase in MT-2 and also a significant increase in CP mRNA with similar kinetics. These parallel increases in MT and CP mRNA suggest that the coordinated expression of these proteins may be important for their synthesis during the acute phase response.z 1999 Federation of European Biochemical Societies.

Cytokine and acute phase protein expression in blood samples of harbour seal pups

“…In 2005, for the most animals, the APP mRNA blood levels decreased during rehabilitation, whichmight be consistent with higher stress level or pathogen impact at admission and/or progressed immune responses at release (Cousins and Leinart, 1988;Daffada and Young, 1999;Heegaard et al, 1998;Murata et al, 2004;Petersen et al, 2004;Sato et al, 1994).…”

Essential Metalloelement Chelates Facilitate Repair of RadiationInjury

“…It is also known that changes in ceruloplasmin (Cp), a Cu-dependent multifunctional plasma enzyme, the plasma Zn containing a2-macroglobulin, and transferrin, the plasma Fe transporter, mediated responses to injury are regulated by IL-1 and other cytokines m facilitating tissue repair processes. Addition of inflammatory cytokines; IL-lt, IL-II or inorganic Cu to hepatocyte culture medium increased mRNA Ibr MT-I, MT-2, and Cp in a coordinated cytokine-activation of hepatic cells as an acute phase response to inflammation [56]. These observations offer a clearer understanding of the well-known cytokine-mediated acute phase response to inflammation and the increase in Cp as an acute phase response to irradiation-induced inflammation.…”

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“…16,17 A close interaction between MT and ceruloplasmin in synthesis and functions has been proposed. 18 Cytoplasmic MT-derived copper may be released by glutathione reduction and then transported into the Golgi or endoplasmic reticulum by the P-type ATPase copper transporter and is incorporated into ceruloplasmin. 10,18 For this mechanism to be relevant in acute phase response, there has to be a coordinated increase in the transcription of MT and ceruloplasmin 18,19 .…”

“…18 Cytoplasmic MT-derived copper may be released by glutathione reduction and then transported into the Golgi or endoplasmic reticulum by the P-type ATPase copper transporter and is incorporated into ceruloplasmin. 10,18 For this mechanism to be relevant in acute phase response, there has to be a coordinated increase in the transcription of MT and ceruloplasmin 18,19 . The modulation of acute phase protein synthesis is primarily achieved through cytokine-induced up-regulation in mRNA expression of the acute phase protein genes in the liver.…”

“…19 It has been reported that MT2mRNA expression and (not MT-1) was induced by IL-1 in the human hepatoma cell line (HePG2 cells) but several others observed that IL-1 indeed induced the synthesis of MT-1, MT-2 and ceruloplasmin expressions. 18,20 Regulation of metallothionein by zinc The most important factor in the modulation of MT is the amount of zinc intake. 21 Zinc deficiency is associated with poor wound healing, growth retardation, hair loss and weak immune function.…”