Bacterial perturbation of cytokine networks

Abstract

From the preceding discussion it is obvious that bacteria have evolved a number of means of inducing and manipulating host cytokine networks. Some mechanisms appear to be very straightforward, involving the production by the organism of potent modulins, such as LPS or exotoxins, which can induce the release of large quantities of proinflammatory cytokines and thereby creating a strong impetus towards the establishment of a cytokine network with a net proinflammatory effect. Others are more subtle, as exemplified by the induction of the release of soluble cytokine receptors. Regardless of the sophistication of the means by which bacteria induce cytokine synthesis, there is overwhelming evidence that bacteria can stimulate the release of (mainly) proinflammatory cytokines. This finding raises the important question mentioned earlier: why are we not in a state of continual inflammation? Although this review has mentioned that bacteria can also suppress cytokine release, the organisms involved have been mainly traditional pathogenic species. What then is the effect of the normal microflora? These organisms certainly have a range of modulins which are potent inducers of proinflammatory cytokine release. It is our view that members of the normal microflora must have surface components (or secreted products) with the ability to downregulate the synthesis of proinflammatory cytokines, to upregulate the release of anti-inflammatory cytokines, or to neutralize the biological activities of proinflammatory cytokines. Alternatively, host cells must be able to affect the activities, or production, of bacterial modulins. The results of a recent study of the ability of a number of gram-positive and gram-negative bacteria to induce the release of certain cytokines from whole human blood are interest (18). Most of the gram-negative species tested (E. coli, Neisseria meningitidis, and Neisseria gonorrhoeae) were between 100-fold and 1,000-fold more potent than the gram-positive species (S. aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Enterococcus faecalis) in inducing the release of the proinflammatory cytokines IL-β and IL-6. Although the gram-negative bacteria also produced more of the anti-inflammatory cytokine IL-1ra, the difference in potencies between the two groups of organisms was slight. So, are these differences due to the different potencies of the modulins of gram-positive and gram-negative bacteria, or is the difference due to the difference abilities of the organisms to neutralize or counteract the activities of proinflammatory cytokine-inducing components? Of particular interest was the finding that Bacteroides fragilis, one of the dominant members of the normal colonic microflora, behaved in a manner identical to that of the gram- positive species (the majority of which are also members of proinflammatory cytokines. We hypothesize that the reason that Bacteroides fragilis, S. aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Enterococcus faecalis produced such low quantities of proinflammatory cytokines is because, being members of the normal microflora, they have evolved means of downregulating the synthesis of proinflammatory cytokines so as to enable them to live (usually) in harmony with their host in contrast to the classic pathogens, N. meningitidis and N. gonorrhoeae. It is our view that understanding the pathology of infectious disease would benefit greatly from fuller investigation of the means by which members of the normal microflora (usually) fail to induce a chronic inflammatory response in their host. An additional benefit may be the discovery of whole new families of anti- inflammatory compounds.