Purpose: Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment, and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-kappa B signaling as a possible cause for excessive inflammation in these patients.
Methods: NF-kappa B signaling was examined by measuring the production of proinflammatory cytokines and evaluating the IRAK1 phosphorylation and degradation as well as the I kappa B alpha degradation upon stimulation with IL-1 beta and TLR agonists in SV40-immortalized fibroblasts, PBMCs, and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively.
Results: Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1 beta and TLR2/6 agonists in immortalized fibroblasts. In PBMCs and whole blood, both patients and controls had a similar response of cytokine production after stimulation with IL-1 beta and TLR4/2/6 agonists. Patients and controls had equivalent patterns of IRAK1 phosphorylation and degradation as well as I kappa B alpha degradation upon stimulation with IL-1 beta.
Conclusion: Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-kappa B signaling in immortalized fibroblasts, PBMCs, and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway.
