Pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IFN-gamma, TNF-alpha) in the plasma correlate with increasing pain intensity. Chronic pain patients show a significant increase in plasma levels of NO in comparison to healthy controls.

Sepsis and septic shock remain major health concerns worldwide, and rapid activation of adrenal steroid release is a key event in the organism's first line of defense during this form of severe illness. Toll-like receptors (TLRs) are critical in the early immune response upon bacterial infection, and recent data from our lab demonstrate a novel link between the innate immune system and the adrenal stress response mediated by TLRs. Glucocorticoids and TLRs regulate each other in a bidirectional way. Bacterial toxins acting through TLRs directly activate adrenocortical steroid release. TLR-2 and TLR-4 are expressed in human and mice adrenals and TLR-2 deficiency is associated with an impaired glucocorticoid response. Furthermore, TLR-2 deficiency in mice is associated with marked cellular alterations in adrenocortical tissue. TLR-2-deficient mice have an impaired adrenal corticosterone release following inflammatory stress induced by bacterial cell wall compounds. This defect appears to be associated with a decrease in systemic and intraadrenal cytokine expression. In conclusion, TLRs play a crucial role in the immune-adrenal crosstalk. This close functional relationship needs to be considered in the treatment of inflammatory diseases requiring an intact adrenal stress response.

Toll-like receptors (TLRs) are key elements in the innate immune response, functioning as pattern-recognition receptors for the detection and response to endotoxins and other microbial ligands. Inflammatory cytokines play an important role in the activation of the hypothalamic-pituitary-adrenal HPA axis during inflammation and sepsis. The newly recognized major role of TLR2 and TLR4 and the adrenal stress response during critical illnesses such as inflammation and sepsis demand comprehensive analysis of their interactions. Therefore, we analyzed TLR2 and TLR4 expression in human adrenal glands. Western blot analysis demonstrated the expression of TLR2 and TLR4 in the human adrenocortical cell line NCI-H295. Immunohistochemical analysis of normal human adrenal glands revealed TLR2 and TLR4 expression in the adrenal cortex, but not in the adrenal medulla. Considering the crucial role of the HPA axis and the innate immune response during acute sepsis or septic shock, elucidating the functional interaction of these systems should be of great clinical relevance.

Although isoflurane preconditioning resulted in a reduction in infarct size at all concentrations used, the protection was mediated by phosphorylation and translocation of PKCepsilon only at 0.4 MAC.

Despite the limitations of an open observational study, our findings suggest that mirtazapine is a safe and well-tolerated drug for use in daily clinical practice. It still remains unclear whether the reduction of pain, the enhancement of the depressed mood or the combination of both effects led to these results. Nevertheless, our data point to a potential beneficial effect of mirtazapine in the treatment of patients with pain and concomitant depression. However, more systematic research, including placebo-controlled studies, and further empirical testing are necessary.

The body’s ability to keep a steady homeostatic state is crucial to health and life. This involves providing an adequate response to a variety of challenges both physical and mental, such as microbial invasion and emotional distress. Interplay between the neuroendocrine and immune systems is essential in either case. Studies have demonstrated that toll-like receptors, or TLRs, play a regulatory role in both systems, and have been proposed as a possible link between the immune, hormonal and metabolic systems. As part of the innate immune system, these receptors control the identification by the body of microbial invaders and its immediate reaction in immune and inflammatory response. What are referred to as pattern recognition receptors are mostly expressed by cells involved in hematopoietic linkage, but an increasing number of studies have demonstrated their expression in other cell types such as neurons and endocrine cells on the hypothalamic-pituitary-adrenal (HPA) axis, thyrocytes, adipocytes and islets of Langerhans. Together with endocrine and metabolic dysregulation, immune system overreaction is often associated with infection and autoimmunity, clearly indicating TLR involvement at organ level which affects organ function. Several diseases such as autoimmune thyroid and pancreatic diseases, septic dysregulation of the HPA axis, diabetes and the metabolic syndrome have been linked to TLR activation and polymorphism. To gain insight into stress response and adaptation, we need to know more about TLRs and the specific physiological role they play in the endocrine and metabolic system and its processes.

Bacterially derived ligands, Pam3CSK4 and LPS, can directly impact adrenal glands steroidogenesis through microdomain-related TLR1/2 and 4, respectively, and indirectly via immune cell-derived cytokines. The bilateral immunoadrenal relationship plays an important role in the proper functioning of both systems. CXC chemokine-dependent immune cell infiltration into adrenocortical carcinomas (ACC), which correlates with poor prognosis, is a common phenomenon. Recently, IL8 was identified in ACC and NCI-H295R cells, and was found to contribute to ACC tumour growth. The aim of this study was to clarify the role of different TLR ligands in IL8 production in NCI-H295R cells. This is the first study to demonstrate the expression of several TLRs including TLR1, 3, 6, 7 and 9 in human adrenocortical cells by using the RT-PCR approach. Only stimulation with TLR1/6 together with TLR2 ligands resulted in IL8 peptide and mRNA induction in a dose and time-dependent manner. Our data suggest that gram-positive bacteria-related TLR1/2/6 ligands might contribute to adrenal gland tumorigenesis via IL8 production.

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