Determination of cytokines involved in initiation of acute inflammation.

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To know the cytokines involved in the development of inflammation. We developed a subtraction gene library of rabbit and detected several candidate cytokines which are specifically expressed during the course of inflammation, i.e.TNFalpha), IL-8, IL-1beta and IL-1ra. Then, we made recombinants and antibodies of these gene products and investigated the significance of these cytokines in the pathogenesis of LPS-induced acute inflammation in rabbits.We conclude the followings :1. TNFalpha and IL-8 were produced during the initial stage (within 2 hrs). The production of these cytokines were mutually independent, namely inhibition of one of these did not suppressed the production of the other. The production was not reduced by depletion of neutrophils. Immunostaining revealed that resident cells were positive for these two cytokines, but not neutrophils.2. IL-1beta was produced during a later stage (peaked at 6 hrs). Production of IL-1beta was induced by both TNFalpha and IL-8 ; namely, inhibition of the two cytokines resulted in reduced production of IL-1beta. Recombinant TNFalpha or IL-8 induced the strong production of IL-1beta.3. IL-1 ra was produced by infiltrated neutrophils and macrophages and suppressed by inhibition of TNFalpha and IL-8. Recombinant IL-1ra suppressed the infiltration of neutrophils. Inhibition of IL-1ra produced enhanced neutrophil infiltration and tissue destruction.4. Inhibition of TNFalpha or IL-8 resulted in a partial inhibition of neutrophil infiltration at an early stage (2 hrs) of inflammation, but not those in a later stage (9 hrs).5. Inhibition of IL-1 resulted in reduced neutrophil infiltration at the later stage of inflammation. Then, we reached a conclusion that both TNFalpha and IL-8 act as initiation of inflammation and IL-1beta play a role in the amplification of acute inflammation.