Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Stress influences circulating inflammatory markers, and these effects may mediate the influence of psychosocial factors on cardiovascular risk and other conditions such as psoriasis and rheumatoid arthritis. Inflammatory responses can be investigated under controlled experimental conditions in humans, and evidence is beginning to emerge showing that circulating inflammatory factors respond to acute psychological stress under laboratory conditions. However, research published to date has varied greatly in the composition of study groups, the timing of samples, assay methods, and the type of challenge imposed. The purpose of this review is to synthesize existing data using meta-analytic techniques. Thirty studies met inclusion criteria. Results showed robust effects for increased levels of circulating IL-6 (r=0.19, p=0.001) and IL-1beta (r=0.58, p<0.001) following acute stress, and marginal effects for CRP (r=0.12, p=0.088). The effects of stress on stimulated cytokine production were less consistent. Significant variation in the inflammatory response was also related to the health status of participants and the timing of post-stress samples. A number of psychobiological mechanisms may underlie responses, including stress-induced reductions in plasma volume, upregulation of synthesis, or enlargement of the cell pool contributing to synthesis. The acute stress-induced inflammatory response may have implications for future health, and has become an important topic of psychoneuroimmunological research.