|
Flagellin
The flagellin subunit of bacterial flagella has emerged as an important mediator of inflammation released by gram negative bacteria. At low concentrations, flagellin has been shown to activate macrophages, monocytes, and intestinal and pulmonary epithelial cells in vitro and induce the release of a variety of pro-inflammatory mediators in vitro and in vivo. The inflammatory mediators produced in vivo in response to flagellin include tumor necrosis factor-a (TNF-a), macrophage inflammatory protein-1a (MIP-1a), interleukin 6 (IL-6), IL-8, IL-12p40, and IL-10 as well as nitric oxide produced by the inducible isoform of nitric oxide synthase (iNOS).
The central downstream pathway mediating flagellin’s pro-inflammatory and immunostimulatory effects involves the activation of TLR5. Flagellin binds to TLR5, culminating in the activation of NF-kappaB which is required for the transcriptional induction of many pro-inflammatory cytokines. The interaction between flagellin and TLR5 is supported by recent studies demonstrating that the presence of a common stop codon polymorphism in the ligand binding domain of TLR5 yields a phenotype that is unable to mediate flagellin signaling. Additionally, the site of flagellin contact with epithelial cell (basolateral versus apical) is thought to play a role in the activation of the pro-inflammatory cascade. This is highlighted in a study demonstrating that basolateral treatment of model intestinal epithelia with flagellin recapitulates the pro-inflammatory gene expression induced by colonization with live Salmonella. Applying flagellin to the apical surface of such epithelia does not induce this induction of pro-inflammatory gene expression.
The neutralization of flagellin may provide significant protection against inflammatory processes induced by flagellated organisms. Clinical conditions that may benefit from such a therapeutic intervention include Crohn’s disease and necrotizing enterocolitis, as well as infectious processes in which a hyper-inflammatory response (e.g. gram negative septic shock, systemic inflammatory response syndrome, acute respiratory distress syndrome) dominates the pathophysiology.
| 
