Modulins: A new class of cytokine-inducing, pro-inflammatory bacterial virulence factor

Abstract

Despite the fact that the inflammatory and immune responses have evolved to combat microorganisms, the present generation of inflammation researchers has evinced relatively little interest, with the exception of septic shock, in microbially-induced inflammation. This in spite of the fact that the Gram-negative cell wall constituent, lipopolysaccharide, has been widely used as a tool in inflammation research. The reason for such lack of interest has been due to the therapeutic efficacy of antibiotics which are the treatment of choice for infections and their inflammatory sequelae. However, this is likely to change within the next decade or so, with the relentless increase in the incidence of antibiotic-resistant strains of bacteria. This will return therapy to the stage where clinicians will have to treat the inflammatory symptoms of infection. Many of these symptoms are due to the stimulation of cytokine synthesis. The capacity of bacteria to induce cytokine synthesis has, until the past few years, centred exclusively on lipopolysaccharide. However, it has been established during the past 5-10 years that a range of other molecules, mainly associated with the surface of bacteria, have the capacity to induce cytokine production. Some of these are exquisitely potent stimulators of pro-inflammatory cytokine synthesis. The nature and mechanism of action of these various cytokine-inducing molecules, for which we have devised the name modulins, is the subject of this review. It is clear that bacteria still have many surprises for us, as exemplified by the recent discovery of the role played by Helicobacter pylori in gastritis, gastric ulceration and gastric cancer.

Sequential generation of cytokines during the initiative phase of inflammation, with reference to neutrophils

“…LPS is considered to promote inflammation through the production of cytokines, such as TNFa, IL-1, and IL-8 [30][31][32]. To better understand how TNFa, IL-1, IL-8, and IL-1Ra are involved in the leukocyte infiltration induced with LPS, we administered neutralizing antibodies or IL-1Ra to inhibit the activities of TNFa, IL-8, IL-1Ra, or IL-1.…”

Modulation of Human T Cell Responses and Macrophage Functions by Onchocystatin, a Secreted Protein of the Filarial NematodeOnchocerca volvulus

“…In addition, B. malayi cystatin inhibits the Ag presentation of human B lymphocyte lines (14). These examples show that nematode components have the potential to interfere with regulatory host immune responses very much like certain pathogenicity factors described from bacterial and protozoan infections (15,16).…”

Modulation of Cytokine Release in Ex Vivo-Stimulated Blood from Borreliosis Patients

“…Examples of the last of these hypotheses are known for viral (21), bacterial (1), and parasitic infections (27); this has led to the concept of microbial cytokine-inducing or -suppressing molecules named modulins (19,20). The effects of Borrelia infection on the acquired immune response have been investigated extensively; the strain-and disease stage-specific production of antibodies (39), as well as the T-cell responses (23), have been analyzed in great detail.…”