TNF-ALPHA IS A PRINCIPAL CYTOKINE INVOLVED IN THE RECRUITMENT OF NK CELLS TO LIVER PARENCHYMA

Isolated murine splenic NK cells and the cultured murine endothelioma cell line, eEND2, were used to study the effects of cytokines on NK ce ll/endothelial cell adhesion. Treatment of eEND2 cells with TNF-alpha induced a marked increase (four- to sevenfold) in adherence of NK cell s, as compared with control cultures of endothelioma cells or eEND2 ce lls treated with IL-1 alpha or IL-6. TNF-alpha induction of NK cell ad herence to eEND2 was dose dependent with rapid kinetics, reaching a ma ximum at concentrations between 10 and 1000 U/ml after a 2-h incubatio n. TNF-alpha treatment of L929 fibroblasts or CL-2 hepatoma cells did not result in increased NK cell adhesion. The concentration range of T NF-alpha that was found to maximally augment NK cell adhesion to eEND2 also induced NK cell chemokinetic activity. The relevance of these in vitro results was subsequently analyzed in vivo. Initial studies conf irmed that a single dose of polyinosinic-polycytidylic acid and poly-L -lysine stabilized in carboxymethyl cellulose (poly-ICLC), augmented h epatic NK activity and resulted in a 2.2-fold increase in the number o f liver-associated NK cells. Concomitant treatment of mice with a TNF- alpha neutralizing antisera eliminated both the hepatic influx of NK c ells and the increase in poly-ICLC-induced liver NK activity. These re sults suggest that TNF-alpha is a principal cytokine involved in the i n vivo recruitment and localization of parenchymal NK cells after trea tment with a biological response modifier, and that this regulation se ems to occur via alterations in NK cell/endothelial cell interactions.