Dual mechanisms of action of interferon-gamma in potentiating responses toLPS in mice - IL1, TNF alpha and IL6 production in serum and hypothermia

IFN gamma potentiates the production of serum cytokines and mortality induc ed by LPS, but these responses do not change in parallel, and the underlyin g mechanisms are not clear. Pretreatment of mice with 15 mu g rrIFN gamma i ntraperitoneally (IP) resulted in potentiation of LPS-induced serum cytokin e production and hypothermia, but these changes depended on the pretreatmen t time and did not occur in parallel. TNF alpha and IL1 beta levels showed peak potentiation after 8-h-IFN gamma pretreatment which may result from a process of sensitization of mechanisms involved in LPS responses. IL6 level s were most markedly potentiated after 3- and 6-h-IFN gamma-pretreatment an d hypothermia was markedly potentiated after 0-8 h pretreatments. These eff ects may result from an additional synergistic action of IFN gamma with oth er mediators when it is present at significant levels earlier after its inj ection, given that IFN gamma had little (hypothermia) or no effect (cytokin es) alone. The degree of potentiation induced by 18-h-IFN gamma pretreatmen t was related to the dose of LPS, the maximum response having been increase d. Two injections of IFN gamma at 42 and 18 h prior to LPS induced greater increases in TNF alpha and ILI beta production than 18-h pretreatment alone , but not in IL6 production or hypothermia. There may be a maximum level of IL6 production which was surpassed under these conditions. These findings suggest that a balance of sensitizing and synergistic actions of IFN gamma with other mediators such as IL1 and TNF alpha, are the major mechanisms un derlying its potentiation of LPS responses in mice. (C) 1999 Elsevier Scien ce Inc. All rights reserved.