In CPPS “the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS. ...This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles.”(1)
Interestingly CPPS improves during summer. Is it because of vitamin D regulation of immune function? Vitamin D is a potent immune regulator. It does e.g. downregulate excessive cellular response by inhibiting IL-12 and upregulating IL-10.
This may indicate CPPS sufferers are low epinephrine excretors (and thus have low IL-10) and have a hypoactive adrenal medulla. Which in turn may sustain a hypoactive SNS and cellular (Th1/Th17 biased) immune response (and thus autoimmunity).
Do CPPS sufferers have a low IL-10 phenotype? Actually it may be so. Shoskes et al and small Chinese study indicates a higher prevalence of low-IL-10 polymorphisms.(2,3) These are also more common in IBS(4), Crohn’s and other diseases. Another small Chinese study indicates the possibility of immune hypoactivity. They found that TGF-beta1 levels are lower and Foxp3 gene expression is defective.(5) IL-8, measured in seminal plasma, has also been found to be higher in CPPS, especially in NIH-IIIa and -IV.(6) NIH-IIIb has slightly elevated inflammatory markers, while –IIIa and IV have distinctly higher levels than IIIb. (The information about inflammatory immune response in CPPS is somewhat confusing, which is probably due to the fact that seasonal variation in disease activity is not accounted for -- in almost all the papers I have read. Vitamin D levels, for one, would have been interesting to know due to its effect on immune activity.)
IL-10 does also regulate IDO(7) expression, which has been proposed to mediate sickness behaviour, in cells derived from the HPA axis, leading to increased tryptophan availability for serotonin and melatonin pathways, which also may explain why CPPS sufferers feel better during summer.(8,9)
Estrogens (specifically E2, 17B-estradiol) has been shown (at female pregnancy levesl) in murine models to cause inflammation of the prostate histologically similar to those found in CP/CPPS (“chronic abacterial prostatitis”). Unfortunately estrogen levels have not been well studied in CPPS patients, but increased conversion to E2 has been found in SLE and RA. E2 has also been found to cause liver inflammation(10), which leads to increased SHBG levels and decreased free testosterone levels. Decreased testosterone should thus lead to amelioration, but other weak androgens may be converted to estrogens and thus sustain an inflammatory process. Unfortunately SHBG levels are also not studied in CPPS.
Andra bloggar om immunity, adrenal, cytokines, Th1/Th2, estrogens, SHBG, IL-6, HPA axis, IDO, IL-10, IL-12, hypoactive adrenal medulla, low epinephrine excretors.
___________________
(1) Elenkov IJ, Kvetnansky R, Hashiramoto A, Bakalov VK, Link AA, Zachman K, Crane M, Jezova D, Rovensky J, Dimitrov MA, Gold PW, Bonini S, Fleisher T, Chrousos GP, Wilder RL. Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans? J Immunol 181(3):1737-1745, 2008.
(2) Peng FH, Yang JR, Peng LK, Xie XB. [Association of gene polymorphisms of cytokine and cytokine receptor with type III prostatitis] Zhonghua Nan Ke Xue 14(12):1069-1071, 2008. English abstract.
(3) Shoskes DA, Albakri Q, Thomas K, Cook D. Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response. J Urol. 168(1):331-335, 2002.
(4) Collins SM. Dysregulation of Peripheral Cytokine Production in Irritable Bowel Syndrome. Am J Gastroenterol 100:2517-2518, 2005.
(5) Wang SG, Bai J, Xi QL, Hu DL, Liu JH, Ye ZQ. [The role of CD4+CD25+ regulatory T cells in the pathogenesis of chronic abacterial prostatitis/chronic pelvic pain syndrome] Zhonghua Yi Xue Za Zhi. 88(40):2838-2841, 2008. English abstract.
(6) Penna G, Mondaini N, Amuchastegui S, Degli Innocenti S, Carini M, Giubilei G, Fibbi B, Colli E, Maggi M, Adorini L. Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in CP/CPPS and BPH. J Eur Uro 51:524-533, 2007.
(7) Indoleamine 2,3-dioxygenase "is an that initiates the oxidative degradation of ... l-tryptophan, along the kynurenine pathway. The local cellular depletion ... may enable the host to inhibit the growth of various infectious pathogens ... IDO also represents an important immune control enzyme ... capable of suppressing local T cell responses to promote immune tolerance under [during] infectious diseases, foetal rejection, organ transplantation, neuropathology, inflammatory and auto-immune disorders and cancer". King NJ, Thomas SR. Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol. 39(12):2167-72 2007.
(8) Tu, H, Rady P, Juelich T, Smith E, Tyring S, Hughes T. Cytokine Regulation of Tryptophan Metabolism in the Hypothalamic-Pituitary-Adrenal (HPA) Axis: Implications for Protective and Toxic Consequences in Neuroendocrine Regulation. Cell Mol Neurobiol 25(3-4):673-680, 2005.
(9) McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate and glia in depression: a literature review. CNS Spectr 13(6):501-510, 2008.
(10) Straub RH. The complex role of estrogens in inflammation. Endocrine reviews 28(5):521-574.
Wednesday, February 24, 2010
Friday, February 19, 2010
The immune-brain-gut-endocrine axis
This is the third installment of my short review of immune function. For part one (basics) see here and part two (vitamin D) see here. A discussion of CPPS and immunity and some other related topics will follow within the next days.
While the existence of communication between the immune system and other bodily organs may seem an obvious proposition it was not so not long ago. It is only during the last 30 years that it has been appreciated that the immune system and especially the brain (or rather certain parts of the brain) and the immune system “talk” with each other. The exchange of information modulates behavioral and physiological responses to immune insults and immune responses to conscious and semi-conscious behavioral responses to environmental stressors.
Two pathways link the brain and the immune system: signaling through nerves (e.g. neocortical-sympathetic axis and brainstem-vagus pathway) of the autonomic nervous system (ANS), and “neuroendocrine humoral outflow via the pituitary” (that is: substances transported by/in blood, lymph, saliva etc) or rather under HPA axis control. The major ANS component involved in this is the sympathetic nervous system (SNS). This connection has also been evidenced by the alteration of immune function through behavioral conditioning (e.g. that stress both can drive a pro- and anti-inflammatory response) and specific brain lesions.
The ANS is further divided in three sub-systems: the sympathetic (or noradrenergic) nervous system, the parasympathetic (or cholinergic) nervous system and the (semi-autonomous) enteric nervous system that lies entirely within the wall of the gastrointestinal tract (a sort of second brain in the belly) and that connects to both the SNS and PSNS (via e.g. the vagus nerve).(1)
During immune challenge (or cellular damage for any reason) or stress (work, social etc) the immune system is similarly activated. Levels of norepinephrine (noradrenalin), CRH, vasopressin and other substances change inducing immune activation. The the individual differences in activation are dependant both on early-life events and genes.(2)
Pro-inflammatory cytokines activate the HPA axis which induces increased plasma concentrations of CRH, vasopressin, ACTH and cathecolamines (e.g. epinephrine and noreepinephrine). Activation of the immune system does also induce fever (not always) and sickness behaviour. That immune cytokines cause sickness behaviour has been amply demonstrated due to cytokine therapy of cancer patients, as the symptoms almost immediately disappear upon discontinuation of treatment. It may be interesting to note that “full blown” sickness behaviour is caused by IL-2 and/or IFN-alpha(3). Of special interest is that the fatigue and irritability, commonly seen in CPPS is “caused” by IFN-alpha (which btw, in conjunction with IFN-beta, is central to anti-viral immune response).
An overactive HPA-axis with concomitant hypercortisolemia, is commonly seen in (cytokine-induced) depression. Some anti-depressants have been shown to induce cytokine suppression (and thus immune suppression and regulation), which is interesting in view of the use of anti-depressants against over-active bladder and other micturition disorders. The exact mechanisms are not fully known.
Other cytokine-“antagonists” used in micturition disorders are etanercept and infliximab (both are TNF-alpha-antagonist). (4)
Human visceral obesity is associated with HPA alterations. Cause and effect are still unclear though, but low testosterone and high glucocorticoids result in increased fat. As visceral fat increases it will suppress testosterone and enhance cortisol. (5)
Other substances affecting the immune system are e.g. prolactin, TSH, GH, GNRH and IGF-1. Hyperprolactinemia has e.g. been observed in 20% of SLE sufferers. Low IGF-1 is associated with cognitive decline and sickness behaviour, and low GH with anxiety and depression. IGF-1 is interesting as excercise increases its ratio visavi pro-inflammatory cytokines. Maybe a reason (in addition to the ussal endorphins) why CPPS sufferers (and others) feel better after excercise?(6)
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, immune brain gut endocrine axis, enteric immune system, vagus nerve, immunity, cytokines.
___________________
(1) Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595-638, 2000.
(2) Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. [2008 CCNP Heinz Lehman Award Paper]. J Psychiatry Neursci 34(1):4-20, 2009.
(3) IFN-beta causes fatigue, depression and “mental fog”. TNF-alpha fatigue and anorexia. IL-2 fatigue, anhedonia (listlessness), dysphoria (depression, anxiety, irritability, restlessness) and “mental fog”. IFN-alpha fatigue, depression, psychomotor slowing, anxiety, social withdrawal, irritability, anorexia and “mental fog”.
(4) Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 29(2):201-217, 2005.
(5) Nieuwenhuizen AG, Rutters F. The HPA axis in the regulation of energy balance.
(6) Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun 21:384-292, 2007.
While the existence of communication between the immune system and other bodily organs may seem an obvious proposition it was not so not long ago. It is only during the last 30 years that it has been appreciated that the immune system and especially the brain (or rather certain parts of the brain) and the immune system “talk” with each other. The exchange of information modulates behavioral and physiological responses to immune insults and immune responses to conscious and semi-conscious behavioral responses to environmental stressors.
Two pathways link the brain and the immune system: signaling through nerves (e.g. neocortical-sympathetic axis and brainstem-vagus pathway) of the autonomic nervous system (ANS), and “neuroendocrine humoral outflow via the pituitary” (that is: substances transported by/in blood, lymph, saliva etc) or rather under HPA axis control. The major ANS component involved in this is the sympathetic nervous system (SNS). This connection has also been evidenced by the alteration of immune function through behavioral conditioning (e.g. that stress both can drive a pro- and anti-inflammatory response) and specific brain lesions.
The ANS is further divided in three sub-systems: the sympathetic (or noradrenergic) nervous system, the parasympathetic (or cholinergic) nervous system and the (semi-autonomous) enteric nervous system that lies entirely within the wall of the gastrointestinal tract (a sort of second brain in the belly) and that connects to both the SNS and PSNS (via e.g. the vagus nerve).(1)
During immune challenge (or cellular damage for any reason) or stress (work, social etc) the immune system is similarly activated. Levels of norepinephrine (noradrenalin), CRH, vasopressin and other substances change inducing immune activation. The the individual differences in activation are dependant both on early-life events and genes.(2)
Pro-inflammatory cytokines activate the HPA axis which induces increased plasma concentrations of CRH, vasopressin, ACTH and cathecolamines (e.g. epinephrine and noreepinephrine). Activation of the immune system does also induce fever (not always) and sickness behaviour. That immune cytokines cause sickness behaviour has been amply demonstrated due to cytokine therapy of cancer patients, as the symptoms almost immediately disappear upon discontinuation of treatment. It may be interesting to note that “full blown” sickness behaviour is caused by IL-2 and/or IFN-alpha(3). Of special interest is that the fatigue and irritability, commonly seen in CPPS is “caused” by IFN-alpha (which btw, in conjunction with IFN-beta, is central to anti-viral immune response).
An overactive HPA-axis with concomitant hypercortisolemia, is commonly seen in (cytokine-induced) depression. Some anti-depressants have been shown to induce cytokine suppression (and thus immune suppression and regulation), which is interesting in view of the use of anti-depressants against over-active bladder and other micturition disorders. The exact mechanisms are not fully known.
Other cytokine-“antagonists” used in micturition disorders are etanercept and infliximab (both are TNF-alpha-antagonist). (4)
Human visceral obesity is associated with HPA alterations. Cause and effect are still unclear though, but low testosterone and high glucocorticoids result in increased fat. As visceral fat increases it will suppress testosterone and enhance cortisol. (5)
Other substances affecting the immune system are e.g. prolactin, TSH, GH, GNRH and IGF-1. Hyperprolactinemia has e.g. been observed in 20% of SLE sufferers. Low IGF-1 is associated with cognitive decline and sickness behaviour, and low GH with anxiety and depression. IGF-1 is interesting as excercise increases its ratio visavi pro-inflammatory cytokines. Maybe a reason (in addition to the ussal endorphins) why CPPS sufferers (and others) feel better after excercise?(6)
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, immune brain gut endocrine axis, enteric immune system, vagus nerve, immunity, cytokines.
___________________
(1) Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595-638, 2000.
(2) Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. [2008 CCNP Heinz Lehman Award Paper]. J Psychiatry Neursci 34(1):4-20, 2009.
(3) IFN-beta causes fatigue, depression and “mental fog”. TNF-alpha fatigue and anorexia. IL-2 fatigue, anhedonia (listlessness), dysphoria (depression, anxiety, irritability, restlessness) and “mental fog”. IFN-alpha fatigue, depression, psychomotor slowing, anxiety, social withdrawal, irritability, anorexia and “mental fog”.
(4) Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 29(2):201-217, 2005.
(5) Nieuwenhuizen AG, Rutters F. The HPA axis in the regulation of energy balance.
(6) Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun 21:384-292, 2007.
Dihydrotestosterone
High levels of the other major male gonadotropin, DHT (dihydrotestosterone), is strongly associated with abdominal obesity. It does also slowly decline with age from a peak value around 45 pmol/L postpuberty to around 28 in octogenarians. The DHT/FT ratio is fairly constant between 0.15 to 0.18 in healthy adult men.(1)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, bukfetma, testosteron, dihydrotestosteron androgener.
_________________
(1) Starka L, Pospisilova H, Hill M. Free testosterone and free dihydrotestosterone throughout the life span of men. Journal of Steroid Biochemistry & Molecular Biology 116:118–120, 2009.
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, bukfetma, testosteron, dihydrotestosteron androgener.
_________________
(1) Starka L, Pospisilova H, Hill M. Free testosterone and free dihydrotestosterone throughout the life span of men. Journal of Steroid Biochemistry & Molecular Biology 116:118–120, 2009.
Sunday, February 14, 2010
Conclusions about sleep in CPPS
The following is speculative, but sleep deprivation caused by nocturia and sleep disturbances due to CPPS effects on the enteric nervous system (and thus in the end on the HPA axis and on sickness behaviour) is probably an important cause of the severe discomfort and psychological effects seen in CPPS. Especially in non-retired individuals who cannot recover lost sleep during daytime because of work duties. The exact directionality of effects is likely complicated. Are the problem driven by HPA axis disturbances or enteric effects, mediated by the vagus nerve, or by the sleep disturbance caused by nocturia. Regardless of the ultimate cause it is well worth finding strategies for getting a good nights sleep. Strategies such as avoiding caffeinated products, chocolate, alcohol, strawberries and other products know to be diuretic. Especially in the evening and late afternoon.
Prostatit, sömn, cytokiner, CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, immunförsvaret, nokturi.
Prostatit, sömn, cytokiner, CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, immunförsvaret, nokturi.
The importance of sleep
While this may seem an off topic it is not. Disrupted sleep is a common feature in CPPS and other disease. Why is sleep important? Because regular and normal sleep is important for immunocomptence. In an elegant study it was shown that: “Species that have evolved longer sleep durations appear to be able to increase investment in their immune system an be better protected from parasites” and “suggest that sleep has a much wider role in disease resistance than is currently appreciated”.(1)
So undisturbed sleep is important for psychological, urological (2) and immunological health. This is also why elite athletes pay much attention to get regular and adequate (about 8 hours) sleep to keep at the top. You should take the same care.
While studies on sleep and immunity etc on humans are somewhat contradictory due to methodological differences and the complexity of the studies, some general associations have been shown.
Mild sleep deprivation is associated with increased activity of e.g the HPA axis and the autonomic sympatho-adrenal system. The first signs of alterations are changes in emotional perception. And there is a connection between disturbed sleep (i.e. apnoea) and psychiatric illness (e.g. ADHD, depression, schizophrenia). And conversely certain disease, notably chronic inflammatory diseases, is associated with sleep disturbances.(3-8)
Well known cytokines in sleep and health are IL-1 and IL-6. Sleep deprivation increases diurnal levels of IL-6, IL-1 and TNF-alfa and decreases cortisol levels thus causing daytime sleepiness, fatigue, disrupted concentration and other problems. IL-6 peaks during normal sleep (and promotes slow wave sleep, aka stage 3 and 4 sleep). (9-10) But too much will cause bad sleep.
As aspirin decreases IL-6 (11) it may both improve sleep during infection and likely worsen sleep in healthy individuals if taken in the evening. (IL-6 peaks around 1900 and 0500, and is at its lowest around 0800 and 2100.) Other cytokines do also affect sleep.
Vagus nerve signaling is important for activation of the immune system, and insults to vagus nerve afferents may activate the immune system in the absence of verifiable infection / pathogens and cause sleep disruption. Severing of the nerve diminishes this response. (12-13)
Obesity, metabolic syndrome and diabetes are associated with increased risk of sleep disturbances and obstructive sleep apnea.
Effects of sleep disruption differ depending on amount of disruption and if it occurs during deep sleep (also called restorative sleep, slow wave sleep, stage 3 and 4) or during REM sleep. A few days of sleep deprivation has been shown to increase viable bacteria in blood and lymphatic systems. Early (14) and slow wave sleep (SWS) is correlated with a shift towards Th1 immunity and late and REM sleep with a Th2 / immunosuppressive shift. Frequent arousals are correlated with increased cortisol, epinephrine (adrenaline) and norepinephrine (noradr…) levels. (15)
During infection time in SWS is increased, while duration of REM slep is decreased in “severe inflammatory states” (chronic fatigue, cancer and auto-immune disease). Shift work is associated with increased infection and prolonged sleep loss in military is associated with changes in “hormonal patterns”.(16)
(See by the way the site www.cfs-recovery.org, if it is still on line, where a chronic fatigue sufferer tells his tale of years of failed attempts to get a diagnosis (wow he must have been a hypochondriac… [this is a sarcasm]) and appropriate treatment, before finally testing himself for sleep apnoea, despite no snoring!! After which he fast recovered… Especially notice the many odd symptoms and problems he got!)
Prostatit, sömn, cytokiner, CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, immunförsvaret, nokturi.
________________
(1) Preston BT, Capellini I, McNamara P, Barton RA, Nunn CL. Parasite resistance and the adaptive significance of sleep. BMC Evol Biol 9:7, 2009 jan 9
(2) Nolan TE, Metheny WP, Smith RP. Unrecognized association of sleep disorders and depression with chronic pelvic pain. South Med J. 1992 Dec;85(12):1181-3.
(3) Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol. 146(2):105-14, 1997.
(4) Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry. 165(7):830-43, 2008.
(5) Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 166(16):1709-15, 2006.
(6) Ellenbogen JM, Hulbert JC, Jiang Y, Stickgold R. The sleeping brain's influence on verbal memory: boosting resistance to interference. PLoS ONE. 2009;4(1):e4117. Epub 2009 Jan 7.
(7) Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted sleep: effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev 12(3):197-210, 2008.
(8) Schroder CM, O'Hara R. Depression and Obstructive Sleep Apnea (OSA). Ann Gen Psychiatry. 2005 Jun 27;4:13.
(9) Opp MR. Cytokines and sleep. Sleep Med Rev 9:355-364, 2005.
(10) Kapsimalis F, Basta M, Varouchakis G, Gourgoulianis K, Vgontzas A, Kryger M. Cytokines and pathological sleep. Sleep Med 9(6):603-614, 2008.
(11) von Känel R, Kudielka BM, Metzenthin P, Helfricht S, Preckel D, Haeberli A, Stutz M, Fischer JE. Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study. Brain Behav Immun. 22(2):150-157, 2008.
(12) Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 102(4):453-462, 2009
(13) Van Der Zanden EP, Boeckxstaens GE, de Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil. 21(1):6-17, 2009.
(14) Refers to the first 1-3 hours of sleep, while late refers to the following 3-5 hours.
(15) Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 13:357-374, 2006.
(16) Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 116:1188-1198, 2005.
So undisturbed sleep is important for psychological, urological (2) and immunological health. This is also why elite athletes pay much attention to get regular and adequate (about 8 hours) sleep to keep at the top. You should take the same care.
While studies on sleep and immunity etc on humans are somewhat contradictory due to methodological differences and the complexity of the studies, some general associations have been shown.
Mild sleep deprivation is associated with increased activity of e.g the HPA axis and the autonomic sympatho-adrenal system. The first signs of alterations are changes in emotional perception. And there is a connection between disturbed sleep (i.e. apnoea) and psychiatric illness (e.g. ADHD, depression, schizophrenia). And conversely certain disease, notably chronic inflammatory diseases, is associated with sleep disturbances.(3-8)
Well known cytokines in sleep and health are IL-1 and IL-6. Sleep deprivation increases diurnal levels of IL-6, IL-1 and TNF-alfa and decreases cortisol levels thus causing daytime sleepiness, fatigue, disrupted concentration and other problems. IL-6 peaks during normal sleep (and promotes slow wave sleep, aka stage 3 and 4 sleep). (9-10) But too much will cause bad sleep.
As aspirin decreases IL-6 (11) it may both improve sleep during infection and likely worsen sleep in healthy individuals if taken in the evening. (IL-6 peaks around 1900 and 0500, and is at its lowest around 0800 and 2100.) Other cytokines do also affect sleep.
Vagus nerve signaling is important for activation of the immune system, and insults to vagus nerve afferents may activate the immune system in the absence of verifiable infection / pathogens and cause sleep disruption. Severing of the nerve diminishes this response. (12-13)
Obesity, metabolic syndrome and diabetes are associated with increased risk of sleep disturbances and obstructive sleep apnea.
Effects of sleep disruption differ depending on amount of disruption and if it occurs during deep sleep (also called restorative sleep, slow wave sleep, stage 3 and 4) or during REM sleep. A few days of sleep deprivation has been shown to increase viable bacteria in blood and lymphatic systems. Early (14) and slow wave sleep (SWS) is correlated with a shift towards Th1 immunity and late and REM sleep with a Th2 / immunosuppressive shift. Frequent arousals are correlated with increased cortisol, epinephrine (adrenaline) and norepinephrine (noradr…) levels. (15)
During infection time in SWS is increased, while duration of REM slep is decreased in “severe inflammatory states” (chronic fatigue, cancer and auto-immune disease). Shift work is associated with increased infection and prolonged sleep loss in military is associated with changes in “hormonal patterns”.(16)
(See by the way the site www.cfs-recovery.org, if it is still on line, where a chronic fatigue sufferer tells his tale of years of failed attempts to get a diagnosis (wow he must have been a hypochondriac… [this is a sarcasm]) and appropriate treatment, before finally testing himself for sleep apnoea, despite no snoring!! After which he fast recovered… Especially notice the many odd symptoms and problems he got!)
Prostatit, sömn, cytokiner, CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, immunförsvaret, nokturi.
________________
(1) Preston BT, Capellini I, McNamara P, Barton RA, Nunn CL. Parasite resistance and the adaptive significance of sleep. BMC Evol Biol 9:7, 2009 jan 9
(2) Nolan TE, Metheny WP, Smith RP. Unrecognized association of sleep disorders and depression with chronic pelvic pain. South Med J. 1992 Dec;85(12):1181-3.
(3) Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol. 146(2):105-14, 1997.
(4) Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry. 165(7):830-43, 2008.
(5) Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 166(16):1709-15, 2006.
(6) Ellenbogen JM, Hulbert JC, Jiang Y, Stickgold R. The sleeping brain's influence on verbal memory: boosting resistance to interference. PLoS ONE. 2009;4(1):e4117. Epub 2009 Jan 7.
(7) Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted sleep: effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev 12(3):197-210, 2008.
(8) Schroder CM, O'Hara R. Depression and Obstructive Sleep Apnea (OSA). Ann Gen Psychiatry. 2005 Jun 27;4:13.
(9) Opp MR. Cytokines and sleep. Sleep Med Rev 9:355-364, 2005.
(10) Kapsimalis F, Basta M, Varouchakis G, Gourgoulianis K, Vgontzas A, Kryger M. Cytokines and pathological sleep. Sleep Med 9(6):603-614, 2008.
(11) von Känel R, Kudielka BM, Metzenthin P, Helfricht S, Preckel D, Haeberli A, Stutz M, Fischer JE. Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study. Brain Behav Immun. 22(2):150-157, 2008.
(12) Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 102(4):453-462, 2009
(13) Van Der Zanden EP, Boeckxstaens GE, de Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil. 21(1):6-17, 2009.
(14) Refers to the first 1-3 hours of sleep, while late refers to the following 3-5 hours.
(15) Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 13:357-374, 2006.
(16) Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 116:1188-1198, 2005.
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