Microbial/host interactions in health and disease: who controls the cytokine network?

The interacting cellular and molecular systems which we classify as immunity and inflammation evolved to protect the organism from exogenous parasites including viruses and bacteria. Cytokines play a pivotal, but paradoxical, role both in immunity and inflammation. These local peptide hormone-like molecules form a major arm of the organisms, defenses against infectious microorganisms but they are also implicated as potent mediators of the pathology of infectious diseases. The apparently lethal effects of interleukin-1 and tumor necrosis factor in experimental septic shock testify to the latter. In the current paradigm, cytokine induction, as a protective or pathological mechanism, is a direct response to the presence of infectious microorganisms. Evidence is now accumulating that cytokines play a much more complex role in the interplay between exogenous microorganisms and the host. For example, it has been established that viruses have evolved pro-active methods of subverting the cytokine network by producing: (i) soluble cytokine receptors which bind and inactivate cytokines, (ii) immunomodulatory cytokine homologues, and (iii) ICE inhibitors. The possibility exists that the major role of these 'viral cytokines' is to neutralize certain host responses. Recent cytokine transgenic knockouts demonstrate that the normal benign response to commensal gut microflora becomes a lethal inflammatory state in the absence of the cytokines interleukin 2 or interleukin 10. The human body contains an enormous number of microorganisms which constitute the normal microflora. It is estimated that the average human contains 10(13) eukaryotic cells but 10(14) bacteria. We propose that the ability of the multicellular organism to live harmoniously with its commensal microflora must depend on mutual signalling involving eukaryotic cytokines and prokaryotic cytokine-like molecules. Such interactive signalling sets up non-inflammatory cytokine networks in tissues which form the background on which responses to infectious microorganisms must be built and related. The capacity of bacteria to induce cytokine synthesis was believed to be due to a small number of components, such as lipopolysaccharide (LPS), which is only active as a complex with host factors (lipopolysaccharide binding protein and CD14). However, it is now clear that bacteria contain and produce a large number of diverse molecules which can selectively induce the synthesis of both pro-inflammatory and immunomodulatory/anti-inflammatory cytokines. Many toxins are potent inducers of cytokine release or synthesis and some can inhibit LPS-induced cell activation. We have introduced the term bacteriokine to describe these bacterial cytokine inducers. The question that has to be addressed therefore is - who controls the cytokine network (eukaryotic or prokaryotic cells) and how is it controlled? It is proposed that an understanding of this question will bring with it an understanding of how to control the pathological inflammatory response and may allow the development of truly effective anti-inflammatory agents.