SYSTEMIC ADMINISTRATION OF RECOMBINANT INTERLEUKIN-6 IN MICE INDUCES PROLIFERATION OF LYMPHOID-CELLS INVIVO

Interleukin-6 (IL-6) is a pleiotropic cytokine and has been shown to support the growth of T and B lymphocytes in the presence of mitogens in vitro. IL-6 can induce human natural killer (NK) and interleukin-2 (IL-2)-induced lymphokine-activated killer cell (LAK) activity in vitro. It can also mediate antitumor effects in various murine models. In order to understand the mechanism of in vivo action, we have investigated the proliferation of lymphoid cells in vivo and the effects on NK, and LAK cell activities in response to IL-6 administration in mice. In vivo proliferation was measured by labeling the DNA of dividing cells with [I-125]iodo-2'-deoxyuridine. C57BL/6 mice were injected ip with either IL-6 or HBSS control two times a day for 3 days and in vivo proliferation was measured. For comparative purpose IL-2 was administered and in vivo effects were analyzed. IL-6 caused significant proliferation of cells mainly in the spleen, while, IL-2 caused proliferation in the lungs, liver, spleen, and kidneys. Pretreatment irradiation (500 rad) of mice abrogated the IL-6-induced proliferation indicating radiosensitive cells are involved. Furthermore, in vivo proliferation was not observed in young nude mice treated with IL-6. To investigate whether the proliferating cells were cytotoxic, we tested for LAK (vs. fresh MCA-102 tumor targets) and NK (vs. Yac-1 tumor targets) activities in the organs of mice treated with IL-6 or IL-2 by 4 h Cr-51-release assay. IL-2 administration induced the generation of LAK activity and increased NK cytotoxicity in various organs, but IL-6 had no effect. Cytofluorometric analysis of splenocytes from IL-6-treated naive mice revealed that absolute number of B cells and in alloantigen-immunized mice absolute number of CD8, CD4, and Thy 1.2+ T cells were increased. IL-2 also increased T cells and ASGM-1-positive cells, however, IL-6 did not increase ASGM-1 cells. These studies indicate that IL-6 can induce the proliferation of endogenous lymphocytes in the spleen and its antitumor effects may not be mediated by LAK and NK cells.