Increased surface toll-like receptor 2 expression in superantigen shock.

OBJECTIVE

Examination of the interaction between gram-positive bacterial superantigens and toll-like receptor 2 (TLR2) in health and critical illness.

DESIGN

Laboratory ex vivo model and prospective clinical, cohort study.

SETTING

Two research laboratories in university hospitals and two intensive care units.

SUBJECTS/PATIENTS: Laboratory study was performed in transfected HeLa cells and primary human monocytes from healthy volunteers. Clinical study used cells from 20 healthy controls and 45 critically ill patients with circulatory shock.

INTERVENTIONS: HeLa cells and purified monocytes were exposed to purified superantigens or isogenic bacterial supernatants and readout obtained by cytokine enzyme-linked immunosorbent assay, flow cytometry, and quantitative real-time polymerase chain reaction. Peripheral blood mononuclear cells from patients with circulatory shock were compared with controls using flow cytometry and measurement of cytokines after ligand exposure.

MEASUREMENTS AND MAIN

RESULTS

Superantigens were unable to signal through ligation by TLR2. However, TLR2 was up-regulated on the surface of primary human monocytes, without detectable TLR2 messenger RNA neosynthesis, by a range of superantigens and superantigen-containing Streptococcus pyogenes supernatants, although not by isogenic superantigen-negative strains. Superantigen mutant constructs with disrupted major histocompatibility complex class II-binding sites did not support TLR2 up-regulation. TLR2 up-regulation was associated with an increase in the proinflammatory response to TLR2 ligands only at high ligand concentrations. TLR2 was up-regulated in a small subset of patients with severe S. pyogenes sepsis but not in patients with any other category of septic or circulatory shock; responses to TLR2 ligands were reduced in all categories of critically ill patient, however.

CONCLUSIONS

Superantigens up-regulate monocyte surface TLR2 expression through major histocompatibility complex class II signaling. Enhanced surface TLR2 expression may be a specific feature of patients with S. pyogenes-induced shock. Importantly, intensity of TLR2 signaling is not necessarily coupled to TLR2 expression when ligand concentrations are low or after onset of critical illness.