Effects of cytokines on the brain and pituitary - Wilkinson & Brown, 2015. Unclear which article the source of this summary exactly is. The authors of the original text have also written an extensive book on neuroendocrinology: An Introduction to Neuroendocrinology.

Effects of cytokines

Cytokines have an influence on the brain and pituitary. The pituitary and target cell hormones affect immune cells via feedback. Messengers of the immune system are called immunomodulators, because they have modulator actions on the brain and endocrine system.

Location of cytokines

Cytokines are also produced by the brain with pro-inflammatory processes. With in situ hybridisation we can localise and quantify cytokine gene expression, in order to prove that a particular cytokine is synthesised in the brain. When the brain tissue is injured or when the blood flow is compromised, cytokines are secreted by brain cells. This is an inflammatory response. When you block the effects of these cytokines you can treat stroke, Alzheimer’s and Parkinson’s disease.

Cytokines can enter the brain through circumventricular organs, because there is no blood-brain barrier here. Another way to pass through the blood-brain barrier is by active transport. Cytokine receptors can be found throughout the brain, such as in the olfactory bulb, dentate gyrus, hippocampus, hypothalamus and choroid plexus. The receptors are seen on neurons, astrocytes and brain tumour cells. There are many subtypes of cytokine receptors. The general type can be found in figure 13.9, p. 99 of the reader.

Neuromodulation

Cytokines are released after peripheral infection, leading to sickness behaviour. An example cytokine is IL-1, which leads to the release of norepinephrine, particularly in the hypothalamus. It also increases tryptophan and the metabolism of serotonin, and modulates hypothalamic function. IL-2 modulates neurotransmitter release and behaviour, growth of neurons and electrical activity of neurons. IL-6 is neuroprotective in that it can prevent apoptosis of neurons. It inhibits the release of glutamate and prevents the spread of excitation in the cerebral cortex. IL-10 is also neuroprotective, by reducing the effects of hypoxia. It also has anti-pyretic activity.

Neuroendocrine system

Cytokines have an influence on the neuroendocrine system, because they act on the hypothalamus, pituitary, adrenal glands and gonads. They also influence thyroid function and recue the secretion of insulin from the pancreas. When interferon is peripherally injected, levels of CRH, ACTH and glucocorticoids increase, just like PRL secretion. GH is increased by intramuscular injection and TSH by intravenous injection.

IL-1 leads to more release of GH, PRL and ACTH, but less release of TSH and LH. It acts on GH at the pituitary, on PRL at the hypothalamus, on ACTH in the brain - such as the anterior pituitary gland - and periphery and on CRH at the paraventricular nucleus of the hypothalamus. IL-1 is a messenger for the brain that the immune system is activated and to trigger a neuroendocrine stress response. So IL-1 raises glucocorticoid levels. However this inhibits the immune response and down-regulates the IL-1 production.

IL-2 acts on the CRH system and increases secretion of ACTH and β-endorphin from the anterior pituitary gland by activating norepinephrine systems in the PVN and median eminence. IL-2 has an inhibitory effect on LH secretion and increases TSH release from the pituitary gland. IL-6 also acts on CRH release in the hypothalamus and ACTH release from the anterior pituitary. It inhibits LH secretion from the pituitary and lowers TSH levels, but heightens GH and PRL levels. It also increases glucocorticoid secretion. Tumor necrosis factor elevates CRH, ACTH and β-endorphin levels. It doesn’t affect GH, but inhibits TSH, LH and PRL.

There are different thymosins. Thymulin acts on the pituitary and stimulates the secretion of ACTH, LH, GH, TSH and PRL. Thymosin β4 increases LH secretion, but doesn’t affect the pituitary. TF5 increase ACTH, β-endorphin and cortisol. The thymus contains a peptide that regulates release of ACTH. Thymosins have an important role in secretion of pituitary hormones and therefore also influence the gonads and adrenal gland.

Peptide hormones

Many immune cells produce peptide hormones identical to the ones the hypothalamus and pituitary gland produce. They are released after immune stimulation from antigens and hormones. most immune cells also have receptors for these peptides. Therefore immune cell peptides have autocrine/paracrine signalling activity.

Immune system

Brain injury adversely affects the immune response, depending on the location of the lesion and if it is in the right or left cortex. It can cause immune depression and a high risk of infection, possibly leading to death. The immune system is innervated by the sympathetic nervous system and norepinephrine. Immune cells contain NE, 5-HT, substance P, VIP and histamine receptors. When neurotransmitter levels in the hypothalamus and brainstem change, this changes the immune responses, because the activity in the autonomic nervous system changes, as well as there is thymus gland stimulation and altered neuroendocrine activity. So drugs altering neurotransmitter levels also change immune responses. T and B cells are influenced by serotonin. Serotonin raises ACTH levels, mediates secretion of PRL, LH and GH and mediates immune responses.

Catecholamines have many effects on the immune system. Dopamine effects depend on the receptor subtype. It can have an effect on lymphocytes and T cells. Dopamine might also interact with prolactin in their action on the immune system. NE and epinephrine have an influence on the immune responses, by being hormones of the adrenal medulla, neurotransmitters in the hypothalamus and brainstem, and being released from the sympathetic nervous system. When brain NE levels decrease, the production of antibodies in response to antigens is impaired. Immune cells might release acetycholine as an autocrine/paracrine signal.

Autonomic nervous system

Effects of norepinephrine of the immune cells are mediated by the β2-adrenergic receptor (β2-AR). Norepinephrine and epinephrine biosynthesised and released by immune cells act as autocrine/paracrine signals. β2-AR stimulation affects the multiplicity function of T cells. β2 -AR can inhibit the cytotoxic behaviour of natural killer cells and the production and secretion of TNF-α and IL-1 in macrophages. Adrenergic stimulation also regulates thymus function. Neuropeptides released by the sympathetic branch of the somatic nervous system regulates immune system function.

Although there is no evidence of cholinergic innervation of the immune system, lymphocytes do release acetylcholine and possess receptors. Therefore acetylcholine might have a role in the immune system. It has an influence on the secretion of cytokines by acting on the nicotine receptors.

Hypothalamus and pituitary hormones

Hypothalamic and pituitary hormones have a modulatory role on immune responses. Oxytocin and vasopressin receptors are found in thymus tissue. It has opposite autocrine/paracrine effects on lymphocyte number. Oxytocin might stimulate the secretion of interferon γ from cytotoxic T cells and regulate the production of hormones by immune cells. Growth hormone receptors are present in immune cells. GH enhances the development of thymic lymphocyte, modulates the production of cytokines and stimulates the development of B cells. When growth hormone is made in immune cells, it influences thymus function in the following ways: enhancing cytokine production, increasing proliferation of thymocytes and migration stimulation of lymphocytes. Lack of growth hormone could lead to immunodeficiency. PRL stimulates, B and natural killer cells and their progenitors, and macrophages and neutrophils. Prolactin and growth hormones can restore thymic function and T cell activity. PRL plays a role in autoimmune diseases.

Thyroid hormones triiodothyronine (T3) and thyroxine (T4) also modulate immune responses. Proliferation of thymocytes and splenocytes increases because of TRH. TRH can also reverse the inhibition effects of glucocorticoids on lymphocytes. IL-2’s effect on natural killer cells and on B cell activity is increased by TSH, which is produced in the immune system. Thyroid hormones keep up the weight of the thymus and the production of thymulin.

Females are more susceptible to develop inflammatory and autoimmune diseases, which might lead to higher immune responses than males have. A possible explanation is that the gonadal sex hormones regulate the immune cell responses and these sex hormones differ between males and females. Immune cells have sex hormone receptors. Another difference between females and males is the macrophage, monocyte and natural killer cell numbers and activity. Women have more circulating antibodies than men, because estradiol increases the output of immunoglobulins in B cells, while testosterone inhibits this. Men have higher levels of monocytes than women. Estradiol and progesterone might have an inhibitory effect on monocyte IL-12 production, because this is reduced during pregnancy. When estradiol is present in low levels, there are more natural killer cells.

Symptoms of diseases worsen during the premenstrual period, because estradiol and progesterone are largely fluctuating in the blood during this period. This variation is important to take into account with implanting an embryo and pregnancy. Another effect of sex steroids is on the thymus. They contribute to thymic involution and immune aging. It might be useful to remove sex hormones for immune system rejuvenation. During pregnancy however thymic atrophy is induced by high levels of estradiol and progesterone and this might be necessary to prevent the rejection of the fetus. After birth this reverses itself.

When the hypothalamic-pituitary-adrenal system is activated by stress we are more sensitive to infections, our responses to vaccines are reduced, recovery from tissue damage slows down and depression can be induced. The adrenal gland produces glucocorticoids and the adrenal medulla epinephrine and norepinephrine. All hormones produced affect the immune system. Glucocorticoids affect the immune system through glucocorticoid receptors. Remember that these are mineralocorticoid (MR) and glucocorticoid (GR) receptors. Glucocorticoids bind at GR in T and B cells, macrophages, monocytes and neutrophils. This can inhibit the function of the immune system and restrain the maturation, differentiation and proliferation of immune cells.

Cytokine gene expression is regulated by glucocorticoids, by suppressing the pro-inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-11, IL-12, TNFα, IFNγ and GM-CSF) and upregulating the anti-inflammatory cytokines (IL-4 and IL-10). Cellular immunity is also reduced by glucocorticoids, because it inhibits the development of the thymus gland, induces atrophy of the thymus and inhibits the development and differentiation of T cells. When corticosteroids are released for a long time it could lead to apoptosis of T cells. Glucocorticoids are used to control inflammation and prevent organ transplant rejection, but can also enhance resistance to infection. The different mechanisms arise because of binding to a different glucocorticoid receptor.

Immediately after an inflammatory or endotoxin insult cytokines are released, even before the release of ACTH. It could be that because of this immune response the CRH-ACTH-glucocorticoid cascade is activated. Glucocorticoids give negative feedback signals to the immune system by immunosuppressive actions. It prevents an out-of-control immune system.

Neuropeptides

Immune system activity is also modulated by neuropeptides, such as substance P, CRH, NPY, prolactin, growth hormone, somatostatin, opioid peptides and VIP. Substance P can bind to T and B cells, monocytes and macrophages, which leads to an increase in cytokine secretion, an increase in trafficking of cells from lymph nodes to the blood and inhibits natural killer cell cytotoxicity. T and B cells, monocytes and macrophages carry receptors for NPY. Effects it can have are: downregulation of antibody production (effect on B cells), modulation of immune cell trafficking, cytokine production, T helper cell differentiation and natural killer cell activity.

CRH binding to T cells and macrophages can increase release of IL-1, IL-6 and TNFα. Prolactin controls progenitor cell proliferation, regulates activation, differentiation and proliferation of T cells and increases generation of IFNγ and TNFα. By binding to T and B cells, macrophages and natural killer cells, growth hormone can increase the activity of natural killer cells, increase the antibody production and stimulate the thymocyte production. Somatostatin receptors can be found on macrophages. It reduces the release of IL-8 and can be immunosuppressive. VIP receptors are present on lymphocytes. The peptide is anti-inflammatory, lessens the generation of IL-2 and the number of lymphocytes.

Hypothalamic integration

Immune responses lead to maintenance of homeostasis, so cytokines have an important role in this. They tell the brain which type of immune response is activated and they regulate this immune response. For coordination of adaptive responses to stress, the brain and immune system communicate via the neuroendocrine-cytokine messenger systems. The hypothalamus integrates the information from these messenger systems. Stressors activate the neuroimmune stress response. This leads to activation of the immune system, production and proliferation of immune cells and altered neurotransmitter release and electrical activity in the hypothalamic neurons. When the hypothalamus is damaged neuroimmune responses and neuroendocrine responses will be abnormal. The paraventricular nucleus (PVN) is the most important area of the hypothalamus in the integration of the neuroendocrine-immune response.

The PVN contains receptors for cytokines and thymic hormones. It is involved in afferent and efferent sympathetic and parasympathetic parts of the autonomic nervous system. The PVN also contains magnocellular neurons to release oxytocin and vasopressin, which act on the thymus gland to influence the development of T cells. The parvicellular neurons of the PVN release TRH, CRH and other hypothalamic hormones, which stimulate endocrine and immune cells. This leads to an increase of gonadal and adrenal steroid hormones modulating the immune system. The glucocorticoids inhibit the immune responses by giving negative feedback. Because the PVN receives input from circumventricular organs without blood-brain barrier, large peptides can pass here between the circulation and brain. The PVN receives input from the neocortex, amygdala and hippocampus, which mediate cognitive functions. Cognitive stressors can influence the immune system through the hypothalamic neuroendocrine-immune integrating mechanisms. The PVN could integrate the cognitive responses to stressful psychosocial stimuli by activating the neuroendocrine-immune system, leading to a psycho-neuro-endocrine-immune system response.

When we have fever because of antigens, the hypothalamus initiates responses from the autonomic nervous system, the neuroendocrine system and behavioural responses. The hypothalamus is also involved in hunger and feeding behaviour by actions of the cytokines. Neuroendocrine functions alter when food intake changes. Cytokines can also lead to cognitive, psychiatric and behavioural side effects. Pituitary hormones have a day/night or sleep/wake rhythm of activity. The suprachiasmatic nuclei of the hypothalamus play a role in this. The hypothalamic neuroendocrine rhythms also control the day/night cycles of immune responses. When these rhythms are disturbed it can cause vulnerability to infection and disease.

Neurotransmitters, peptide hormones and cytokines can activate second messenger systems in target cells. Ion channels and receptors in the target cells are regulated by the second messengers. It also leads to transcription of genomic information. Besides this, receptor and second messenger mechanisms mediate the interactions between neural, endocrine and immune systems. Hormones, neurotransmitters and peptides may interact to regulate the immune responses to antigens. Neurons can produce cytokines for their target cells, namely macrophages.