Leukocyte cytokine responses in adult patients with mitochondrial DNA defects

AbstractPatients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A >  G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose–r esponse experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74 –79% lower responses for IL-6 and IL-1β (pIL-6 = 0.031, pIL-1 β = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A >  G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocortic oids. Further work in larger cohorts is needed to...
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research