Synergistic stimulation by anaphylatoxin C5a and endotoxin of the release of the proinflammatory cytokine IL-6 from Kupffer cells: Role in alpha 2-macroglobulin synthesis during the acute phase response in hepatocytes

Hepatocytes support systemic or local immune responses by an enhanced relea se of glucose and an altered synthesis of acute phase proteins (APP). Gluco se release is mediated by prostanoids and APP synthesis by cytokines. Lipop olysaccharide (LPS) as a classical" trigger" of inflammatory responses has been shown to induce the release of prostanoids as well as of cytokines fro m Kupffer cells (KC), while the anaphylatoxin C5a, which is generated durin g activation of the complement system has been reported so far only to enha nce the release of prostanoids. It is shown here that recombinant rat C5a ( rrC5a) induced the expression of TNF-alpha mRNA and IL-1 beta mRNA but not of IL-6 mRNA in rat KC. However rrC5a synergistically enhanced LPS-induced IL-6 mRNA synthesis. Since among the proinflammatory cytokines IL-6 is the major inducer of APP, it was further investigated whether C5a- and/or LPS-s timulated rat KC indirectly induced the synthesis of APP in rat hepatocytes (HC). Conditioned media of LPS- but not of rrC5a-treated KC induced alpha 2-macroglobulin mRNA expression in HC, bur media of rrC5a- plus LPS-treated KC were much more effective than LPS-treated media alone. Thus, C5a is not only involved in the regulation of prostanoid release from KC enhancing gl ucose output from HC, but also of cytokine formation by KC stimulating APP synthesis in HC.