MicroRNA-mediated regulation of IL-10, IL-12 and TNFα gene expression in severely injured trauma patients
© Jones et al. 2015
Published: 11 September 2015
Severe trauma induces a blunted immune response associated with an enhanced susceptibility to nosocomial infections . Within 2 hours of injury, expression of the prototypical anti-inflammatory cytokine, IL-10, increases whilst expression of the pro-inflammatory cytokines, TNFα and IL-12, decreases . We hypothesise that microRNAs (miRs) may exacerbate this immunosuppressive gene expression pattern.
Following ethical approval and consent, 30 ICU patients admitted following trauma and 16 healthy age and sex-matched controls were recruited. Blood samples were obtained within 2 hours of injury and at 24 hours. miRs were isolated using PAXGene (Qiagen). miRs were selected on the basis of their miRBase target prediction scores for the promoters of IL-10, IL-12 and TNFα. Six miRs selected for analysis were miR374b, -202 and 125a3p (IL-10), -410 and -21 (IL-12) and -454 (TNFα). qPCR was used to quantify candidate miRs and the results were normalised relative to small nucleolar RNAs U6/RNU44. Infections were assessed using predefined criteria .
Twenty three patients (77%) developed an infection, 15 (50%) were shocked (base deficit ≥ 6 mEq/L) on admission and 6 (20%) died. Within 2 hours, expressions of miR-202, -125a3p, -21 and -454 were reduced (all p<0.03) in patients compared to healthy controls. This reduction was maintained (all p<0.01) 24 hours after injury. At 24 hours, miR-202 was down-regulated (2.4-fold, p=0.01) in shocked compared to non-shocked patients. Decreased miR-374b expression on admission was associated with subsequent development of pneumonia (p=0.009).
Expression of miRs complementary to cytokine promoters varies significantly following severe traumatic injury and is associated with clinical outcomes. Reduction in inhibitory miRs could partly explain increased IL-10 expression and provide a mechanistic link between severe trauma, the observed immunosuppressive phenotype and an increased incidence of nosocomial infections. In vitro studies are now needed to invoke causation.
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