Potentially fatal physiologic and metabolic derangements can occur in response to
bacterial infection in animals and man. Recently it has been shown that alterations in the levels of circulating
cytokines such as
IL-6 and
TNF-alpha occur shortly after bacterial challenge. To understand better the role of
IL-6 in
inflammation, we investigated the effects of in vivo anti-mouse
IL-6 antibody treatment in a mouse model of
septic shock. Rat anti-mouse
IL-6 neutralizing mAb was produced from splenocytes of an animal immunized with mouse rIL-6. This mAb, MP5-20F3, was a very potent and specific antagonist of mouse
IL-6 in vitro bioactivity, demonstrated using the NFS60 myelomonocytic and KD83
plasmacytoma target cell lines, and also immunoprecipitated radiolabeled
IL-6. Anti-IL-6 mAb pretreatment of mice subsequently challenged with lethal doses of i.p. Escherichia coli or i.v.
TNF-alpha protected mice from death caused by these treatments. Pretreatment of E. coli-challenged mice with anti-IL-6 led to an increase in serum TNF bioactivity, in comparison to isotype control antibody, implicating
IL-6 as a negative modulator of TNF in vivo. Anti-
TNF-alpha treatment of mice challenged i.p. with live E. coli resulted in a 70% decrease in serum
IL-6 levels, determined by immunoenzymetric assay, compared to control antibody, thereby supporting a role for
TNF-alpha as a positive regulator of
IL-6 levels. We conclude that
IL-6 is a mediator in lethal E. coli
infection, and suggest that antagonists of
IL-6 may be beneficial therapeutically in life-threatening
bacterial infection.