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Toll-Like Receptor 9 Expression in Murine and Human Adrenal Glands and Possible Implications during Inflammation

Molecular Cardioprotection and Inflammation Group (R.B., O.B., K.Z.), Department of Anaesthesia and Department of Endocrinology, Diabetes, Rheumatology (M.S.), University Hospital Dusseldorf, 40225 Dusseldorf, Germany; Department of Anaesthesia (N.T., A.K., P.A.Z., K.Z.), Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom; Department of Anaesthesia (G.B., P.K.), University Hospital Bonn, 53105 Bonn, Germany; Department of Medicine (W.K., S.R.B.), University of Dresden, 01307 Dresden, Germany; and Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (S.L.L.), Bristol BS1 3NY, United Kingdom

Address all correspondence and requests for reprints to: Professor Kai Zacharowski, M.D., Ph.D., Molecular Cardioprotection and Inflammation Group, Department of Anesthesia, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail: kai.zacharowski{at}bristol.ac.uk.

Context: Sepsis is a leading cause of death in the Western world and can be associated with failure of the hypothalamic-pituitary-adrenal axis. A coordinated response of the adrenal and immune system is of vital importance for survival during sepsis. Within the immune response, Toll-like receptors (TLRs) play a crucial role by recognizing pathogen-associated molecules such as bacterial DNA. TLR-9 can detect motifs of unmethylated cytosine-phosphate-guanine (CpG) dinucleotides (CpG-DNA) being present in bacterial DNA.

Objective: We investigated whether TLR-9 is expressed in human and murine adrenal glands and whether its activation is associated with an adrenal response.

Design: Human fetal and adult adrenal glands; wild-type, C57BL/6 and TLR-9 deficient (TLR-9^–/–) mice; and in vitro cell line models were used in the study.

Setting: The study took place at a university hospital.

Results: TLR-9 is expressed in human and murine adrenal glands, as well as in in vitro cell lines (Y-1 and NCI-H295R cells). CpG-oligodeoxynucleotide challenge caused a 3-fold increase in plasma levels of corticosterone in wild-type mice. This effect was not observed in TLR-9^–/– mice. Furthermore, CpG-oligodeoxynucleotide challenge resulted in a strong release of several inflammatory cytokines, such as TNF-, and IL-1ß, -6, -10, and -12 in vivo as well as in vitro. Again, this effect was not present in TLR-9^–/– mice.

Conclusions: TLR-9 is present in both murine and human adrenal glands. TLR-9 stimulation led to a corticosterone and inflammatory cytokine response. TLR-9 may play a role in the regulation of the hypothalamic-pituitary-adrenal axis during conditions in which bacterial DNA is present.