The intestinal microflora regulates cytokine production positively in spleen-derived macrophages but negatively in bone marrow-derived macrophages

Besides its role as a barrier against potential pathogens, intestinal flora is presumed to protect the host by priming the immunological defense mecha nisms. In this respect, the influence of intestinal flora on macrophage pre cursors was examined, and its modulating effect was compared on LPS-induced cytokine production by macrophages derived from bone marrow and spleen pre cursors (BMDM and SDM respectively), The regulation of IL-1, IL-6, TNF-alph a and IL-12 production in macrophages from germ-free and from three groups of flora-associated mice, conventional, conventionalized and E. coli-mono-a ssociated mice, was investigated. The whole flora inhibited IL-1, TNF-alpha and IL-12 secretion by BMDM, whereas it had a stimulatory effect on IL-12 secretion by SDM. Implantation of E. coli alone enhanced cytokine secretion by BMDM but had a more limited effect than whole flora on SDM, enhancing o nly TNF-alpha and IL-12 secretion. Study of expression of mRNA showed a cor relation with protein secretion for IL-6 but not for TNF-alpha and IL-1, IL -12 enhancement in BMDM seemed to be dependent on regulation of p35 mRNA ex pression while it was correlated to increased p40 mRNA expression in SDM. T he results demonstrated that intestinal flora modulated bone marrow and spl een macrophage cytokine production in a differential manner and suggested a role for bacteria other than E. coli among the whole flora. The contrastin g effects exerted by the intestinal flora on bone marrow and spleen precurs ors are an interesting observation in view of the different functions of th ese organs in immunity. The finding that intestinal flora enhanced IL-12 pr oduction in spleen is also potentially important since this cytokine is imp licated in the determination of the relative levels of Th1 and Th2 response s and plays a pivotal role in host defense against intracellular microorgan isms.