| Popis: |
Exposure to subacute levels of O3 causes decreased lung function, and airway hyperresponsiveness in 10-20% of the human population. Interindividual responses to O3 vary greatly, which suggests a genetic component. O3-induced inflammation results from activation of the innate immune response via specific receptors such as Toll-like receptor 4 (TLR4). TLR4 activation leads to production of soluble mediators such as interleukins (IL)-12, IL-18, and IL-10 that can affect immune responses. However, the mechanism underlying TLR4-mediated responses as well as the contribution of variants in these specific innate immune response mediators have not been investigated in the inflammatory response to O3. We hypothesized that specific innate immune response mediators confer differential susceptibility to O3-induced inflammation in inbred mice. Studies with Tlr4-mutated (C3H/HeJ) and Tlr4-sufficient (C3H/HeOuJ) mice verified a role for TLR4 in O3-induced hyperpermeability and neutrophilic responses (Kleeberger et al., 2000) but the underlying mechanism remains unclear. The accessory molecule CD14 is critical for TLR4-mediated responses to LPS. However, results from studies using Cd14 gene-deleted mice were negative and indicated that CD14 is not required for the response to O3. The downstream mediator IL-12 was found to contribute to O3-induced inflammation while IL-18 receptor was protective. Moreover, O3-induced neutrophilic inflammation was dramatically increased in mice lacking IL-10, an important anti-inflammatory cytokine, suggesting that IL-10 can potently attenuate neutrophilic influx in response to O3. Together these results suggest that the mechanism underlying O3-induced inflammation occurs independently of CD14 and that the cytokine milieu of the lung can alter the severity of inflammation in response to O3. The complex interplay of multiple genetic contributors must be considered to gain further insight into how inflammation is regulated in response to O3. |
