Endocrine Abstracts (2008) 16 P56

The role of toll-like receptors in adrenal gland inflammatory response and tumorigenesis

Waldemar Kanczkowski1, Henning Morawietz3, Kai Zacharowski2, Christian G Ziegler1, Monika Ehrhart-Bornstein1 & Stephan R Bornstein1

1Department of Medicine, Medicine Clinik III, Carl Gustav Carus University Hospital, Dresden, Germany; 2Molecular Cardioprotection and Inflammation Group, Bristol Royal Infirmary, Bristol, UK; 3Department of Medicine, Medicine Clinic III, Carl Gustav Carus University Hospital, Dresden, Germany.

Sepsis and septic shock remain a major health concern worldwide, and an intact adrenal cortex glucocorticoid (GC) stress response, is critical for organism to survive. Recently, we and others have shown that adrenal gland expresses members of toll-like receptors (TLRs) family which are known to sense pathogens and induce inflammatory response. Data performed on TLRs deficient mice clearly demonstrate a critical involvement of these receptors in immune-neuroendocrine bidirectional crosstalk during infection. TLR-2 and -4 deficient animals developed an impaired GCs response with cytokine dysregulation and ultrastructural impairments of adrenocortical cells. However, the exact mechanism of TLR-mediated adrenal gland dysfunction during bacterial infections is not clear.

Therefore, the aim of this work was to elucidate adrenal gland inflammatory and hormonal response to multiple bacterial-derived ligands, utilising adrenocortical cell line and human cells in primary culture. We found that both human primary adrenocortical cells and NCI-H295R – carcinoma cell line express several TLRs. However, both cell types responded to bacterial-derived ligands differentially. In opposite to NCI-H295R carcinoma cells, adrenocortical cells in primary culture responded to lipopolysaccharide (LPS) and lipoteichonic acid (LTA) stimulation with an enhanced IL-6 and TNF-alpha cytokines and cortisol secretion. Interestingly, the stimulation of adrenocortical carcinoma cells with TLR-1/6 together with TLR-2 ligands (Pam3Cys4 or LTA) resulted in a dose and time dependent induction of IL-8, which in turn was not present in non-transformed cells. In conclusion, our data show that TLRs may contribute to adrenal gland dysfunction during systemic or chronic infections by sustaining an excessive inflammatory response. Additionally, TLRs may contribute to the adrenal gland tumorigenesis by inducing of CXC-chemokines secretion such as IL-8, which are found to be overexpressed in adrenocortical carcinomas (ACC) and to contribute to tumour growth.

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