Cytokine signaling in the modulation of post-acute and chronic systemic inflammation: a review of the influence of exercise and certain drugs

Stephen C Allen; Stephen C Allen

doi:10.3934/Allergy.2020009

AIMS Allergy and Immunology

2020, Volume 4, Issue 4: 100-116. doi: 10.3934/Allergy.2020009

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Cytokine signaling in the modulation of post-acute and chronic systemic inflammation: a review of the influence of exercise and certain drugs

Stephen C Allen ^{1,2
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1.
The Royal Bournemouth Hospital, Castle Lane East, Bournemouth, Dorset BH7 7DW, UK
2.
Centre for Postgraduate Medical Education and Research, Bournemouth University, Bournemouth, Dorset BH12 5BB, UK

Received: 12 July 2020 Accepted: 12 October 2020 Published: 12 October 2020

Acute inflammation in response to stimuli such as infection can be of deleterious amplitude and/or duration in some individuals and often tends towards chronicity in older adults. This inflammatory pattern appears to be causally linked to higher all-cause mortality and other adverse outcomes such as frailty, sarcopenia, mood disorders and impaired cognitive function. Patients in this clinical state have a persistent pro-inflammatory cytokine profile. Exercise has been shown to shift baseline levels of tumor necrosis factor (TNF), interleukin-1 (IL-1) and other cytokines to a less inflamed setting, with interleukin-6 (IL-6) playing a key modulating role. Drugs can also modulate innate immune cells and their biochemical networks with a shift to a surveillance pattern. Theophylline and chloroquine are examples of drugs that could have clinical value as immune modulators. For example, theophylline induces a 20 percent fall in TNF and around 200 percent increase in IL-10 production by blood-harvested mononuclear cells, and a fall of about 50 percent in interferon-gamma (IF-γ) release. Pharmacological activity in that domain could be exploited in clinical practice, with the aim of establishing a less pro-inflammatory innate immune milieu after provocations such as infection, trauma or major surgery.
- infection,
- inflammation,
- innate immunity,
- cytokines,
- exercise,
- anti-inflammatory drugs,
- immune modulation
Citation: Stephen C Allen. Cytokine signaling in the modulation of post-acute and chronic systemic inflammation: a review of the influence of exercise and certain drugs[J]. AIMS Allergy and Immunology, 2020, 4(4): 100-116. doi: 10.3934/Allergy.2020009

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Abstract

Acute inflammation in response to stimuli such as infection can be of deleterious amplitude and/or duration in some individuals and often tends towards chronicity in older adults. This inflammatory pattern appears to be causally linked to higher all-cause mortality and other adverse outcomes such as frailty, sarcopenia, mood disorders and impaired cognitive function. Patients in this clinical state have a persistent pro-inflammatory cytokine profile. Exercise has been shown to shift baseline levels of tumor necrosis factor (TNF), interleukin-1 (IL-1) and other cytokines to a less inflamed setting, with interleukin-6 (IL-6) playing a key modulating role. Drugs can also modulate innate immune cells and their biochemical networks with a shift to a surveillance pattern. Theophylline and chloroquine are examples of drugs that could have clinical value as immune modulators. For example, theophylline induces a 20 percent fall in TNF and around 200 percent increase in IL-10 production by blood-harvested mononuclear cells, and a fall of about 50 percent in interferon-gamma (IF-γ) release. Pharmacological activity in that domain could be exploited in clinical practice, with the aim of establishing a less pro-inflammatory innate immune milieu after provocations such as infection, trauma or major surgery.

Conflict of interest

The author declares no conflict of interest.

References

[1]	Rockwood K, Howlett SE (2018) Fifteen years of progress in understanding frailty and health in aging. BMC Med 16: 220. doi: 10.1186/s12916-018-1223-3
[2]	Nelke C, Dziewas R, Minnerup J, et al. (2019) Skeletal muscle as potential central link between sarcopenia and immune senescence. EBioMedicine 49: 381-388. doi: 10.1016/j.ebiom.2019.10.034
[3]	Howcroft TK, Campisi J, Louis GB, et al. (2013) The role of inflammation in age-related disease. Aging 5: 84-93. doi: 10.18632/aging.100531
[4]	Giacconi R, Malavolta M, Costarelli L, et al. (2015) Cellular senescence and inflammatory burden as determinants of mortality in elderly people until extreme old age. EBioMedicine 2: 1316-1317. doi: 10.1016/j.ebiom.2015.09.015
[5]	Degens H (2019) Human ageing: impact on muscle force and power. Muscle and Exercise Physiology London: Academic Press, 423-432. doi: 10.1016/B978-0-12-814593-7.00019-0
[6]	Brüünsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23: 15-39. doi: 10.1016/S0889-8561(02)00056-5
[7]	Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69: S4-S9. doi: 10.1093/gerona/glu057
[8]	Wener MH, Daum PR, McQuillan GM (2000) The influence of age, sex and race on the upper reference limit of serum C-reactive protein concentration. J Rheumatol 27: 2351-2359.
[9]	Chung HY, Cesari M, Anton S, et al. (2009) Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Res Rev 8: 18-30. doi: 10.1016/j.arr.2008.07.002
[10]	Caspersen CJ, Pereira MA, Curran KM (2000) Changes in physical activity patterns in the United States, by sex and cross-sectional age. Med Sci Sports Exercise 32: 1601-1609. doi: 10.1097/00005768-200009000-00013
[11]	Driver JA, Djousse L, Logroscino G, et al. (2008) Incidence of cardiovascular disease and cancer in advanced age: Prospective cohort study. BMJ 337: a2467. doi: 10.1136/bmj.a2467
[12]	Cowie CC, Rust KF, Byrd-Holt DD, et al. (2006) Prevalence of diabetes and impaired fasting glucose in adults in the US population: NHANES survey 1999–2002. Diabetes Care 29: 1263-1268. doi: 10.2337/dc06-0062
[13]	Starr ME, Saito H (2014) Sepsis in old age: Review of human and animal studies. Aging Dis 5: 126-136.
[14]	Boyd AR, Orihuela CJ (2011) Dysregulated inflammation as a risk factor for pneumonia in the elderly. Aging Dis 2: 487-500.
[15]	Kalaria RN, Maestre GE, Arizaga R, et al. (2008) Alzheimer's disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol 7: 812-826. doi: 10.1016/S1474-4422(08)70169-8
[16]	Coresh J, Selvin E, Stevens LA, et al. (2007) Prevalence of chronic kidney disease in the United States. JAMA 298: 2038-2047. doi: 10.1001/jama.298.17.2038
[17]	Dagenais S, Garbedian S, Wai EK (2009) Systematic review of the prevalence of radiographic primary hip osteoarthritis. Clin Orthop Relat Res 467: 623-637. doi: 10.1007/s11999-008-0625-5
[18]	Ballou SP, Lozanski FB, Hodder S, et al. (1996) Quantitative and qualitative alterations of acute-phase proteins in healthy elderly persons. Age Ageing 25: 224-230. doi: 10.1093/ageing/25.3.224
[19]	Ershler WB, Sun WH, Binkley N, et al. (1993) Interleukin-6 and aging: Blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12: 225-230.
[20]	Wei J, Xu H, Davies JL, et al. (1992) Increase in plasma IL-6 concentration with age in healthy subjects. Life Sci 51: 1953-1956. doi: 10.1016/0024-3205(92)90112-3
[21]	Ahluwalia N, Mastro AM, Ball R, et al. (2001) Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women. Mech Ageing Dev 122: 1269-1279. doi: 10.1016/S0047-6374(01)00266-4
[22]	Beharka AA, Meydani M, Wu D, et al. (2001) Interleukin-6 production does not increase with age. J Gerontol A Biol Sci Med Sci 56: 81-88. doi: 10.1093/gerona/56.2.B81
[23]	Kabagambe EK, Judd SE, Howard VJ, et al. (2011) Inflammation biomarkers and risk of all-cause mortality in the RCARDS cohort. Am J Epidemiol 174: 284-292. doi: 10.1093/aje/kwr085
[24]	DeMartinis M, Franceschi C, Monti D, et al. (2006) Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol 80: 219-227. doi: 10.1016/j.yexmp.2005.11.004
[25]	Jensen GL (2008) Inflammation: Roles in aging and sarcopenia. JPEN J Parenter Enteral Nutr 32: 656-659. doi: 10.1177/0148607108324585
[26]	Penninx BW, Kritchevsky SB, Newman AB, et al. (2004) Inflammatory markers and incident mobility limitation in the elderly. J Am Geriatr Soc 52: 1105-1113. doi: 10.1111/j.1532-5415.2004.52308.x
[27]	Christian LM, Glaser R, Porter K, et al. (2011) Poorer self-related health is associated with elevated inflammatory markers among older adults. Psychoneuroendocrinology 36: 1495-1504. doi: 10.1016/j.psyneuen.2011.04.003
[28]	Michaud M, Balardy L, Moulis G, et al. (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14: 877-882. doi: 10.1016/j.jamda.2013.05.009
[29]	Golbidi S, Laher I (2013) Exercise and the aging endothelium. J Diabetes Res 2013: 1-12. doi: 10.1155/2013/789607
[30]	Bruunsgaard H, Skinhoj P, Qvist J, et al. (1999) Elderly humans show prolonged in vivo inflammatory activity during pneumococcal infections. J Infect Dis 180: 551-554. doi: 10.1086/314873
[31]	Krabbe KS, Bruunsgaard H, Hansen CM, et al. (2001) Ageing is associated with a prolonged fever in human endotoxemia. Clin Diagn Lab Immunol 8: 333-338. doi: 10.1128/CDLI.8.2.333-338.2001
[32]	Wu J, Xia S, Kalonis B, et al. (2014) The role of oxidative stress and inflammation in cardiovascular aging. BioMed Res Int 2014: 1-13.
[33]	McFarlin BK, Flynn MG, Campbell W, et al. (2006) Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. J Gerontol A Biol Sci Med Sci 61: 388-393. doi: 10.1093/gerona/61.4.388
[34]	Rotman-Pikielny P, Roash V, Chen O, et al. (2006) Serum cortisol levels in patients admitted to the department of medicine: Prognostic correlations and effects of age, infection and co-morbidity. Am J Med Sci 332: 61-67. doi: 10.1097/00000441-200608000-00002
[35]	Johnson DB, Kip KE, Marroquin OC, et al. (2004) Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women. Circulation 109: 726-732. doi: 10.1161/01.CIR.0000115516.54550.B1
[36]	Beavers KM, Brinkley TE, Nicklas BJ (2010) Effect of exercise training on chronic inflammation. Clin Chim Acta 411: 785-793. doi: 10.1016/j.cca.2010.02.069
[37]	Everett BM, Bansal S, Rifai N, et al. (2009) Interleukin-18 and the risk of future cardiovascular disease among initially healthy women. Atherosclerosis 202: 282-288. doi: 10.1016/j.atherosclerosis.2008.04.015
[38]	Gokkusu C, Aydin M, Ozkok E, et al. (2010) Influences of genetic variants in interleukin-15 gene and interleukin-15 levels on coronary heart disease. Cytokine 49: 58-63. doi: 10.1016/j.cyto.2009.09.004
[39]	Caruso DJ, Carmack AJ, Lockeshwar VB, et al. (2008) Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence. Clin Cancer Res 14: 4111-4118. doi: 10.1158/1078-0432.CCR-08-0738
[40]	Pan W, Stone KP, Hsuchou H, et al. (2011) Cytokine signaling modulates blood-brain barrier function. Curr Pharm Des 17: 3729-3740. doi: 10.2174/138161211798220918
[41]	Allison DJ, Ditor DS (2014) The common inflammatory etiology of depression and cognitive impairment: A therapeutic target. J Neuroinflammation 11: 1-12. doi: 10.1186/s12974-014-0151-1
[42]	Tizard I (2008) Sickness behaviour, its mechanisms and significance. Anim Health Res Rev 9: 87-99. doi: 10.1017/S1466252308001448
[43]	Zoladz JA, Majerczak J, Zeligowska E, et al. (2014) Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson's disease patients. J Physiol Pharmacol 65: 441-448.
[44]	Ohman H, Savikko N, Strandberg TE, et al. (2014) Effect of physical exercise on cognitive performance in older adults with mild cognitive impairment or dementia: A systematic review. Dementia Geriatr Cognit Disord 38: 347-365. doi: 10.1159/000365388
[45]	Vinik AI, Erbas T, Casellini CMJ (2013) Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Invest 4: 4-18. doi: 10.1111/jdi.12042
[46]	Tishler M, Caspi D, Yaron M (1985) C-reactive protein levels in patients with rheumatoid arthritis. Clin Rheumatol 4: 321-324. doi: 10.1007/BF02031616
[47]	Pal M, Febbraio MA, Whitham M (2014) From cytokine to myokine: The emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol 92: 331-339. doi: 10.1038/icb.2014.16
[48]	Pedersen BK, Febbraio M (2005) Muscle-derived interleukin-6: A possible link between skeletal muscle, adipose tissue, liver and brain. Brain Behav Immun 19: 371-376. doi: 10.1016/j.bbi.2005.04.008
[49]	Kishimoto T (2010) IL-6: From its discovery to clinical applications. Int Immunol 22: 347-352. doi: 10.1093/intimm/dxq030
[50]	Mikkelsen UR, Couppe C, Karlsen A, et al. (2013) Life-long endurance exercise in humans: Circulating levels of inflammatory markers and leg muscle size. Mech Ageing Dev 134: 531-540. doi: 10.1016/j.mad.2013.11.004
[51]	Pedersen BK, Steensberg A, Fischer C, et al. (2003) Searching for the exercise factor: Is IL-6 a candidate? J Muscle Res Cell Motil 24: 113-119. doi: 10.1023/A:1026070911202
[52]	Pedersen AMW, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol 98: 1154-1162. doi: 10.1152/japplphysiol.00164.2004
[53]	Wojewoda M, Kmiecik K, Majerczak J, et al. (2015) Skeletal muscle response to endurance training in IL-6^-/- mice. Int J Sports Med 36: 1163-1169. doi: 10.1055/s-0035-1555851
[54]	Fischer CP (2006) Interleukin-6 in acute exercise and training; what is the biological relevance? Exerc Immunol Rev 12: 6-33.
[55]	Woods JA, Veira VJ, Keylock KT (2009) Exercise, inflammation and innate immunity. Immunol Allergy Clin North Am 29: 381-393. doi: 10.1016/j.iac.2009.02.011
[56]	Pedersen BK (2011) Exercise-induced myokines and their role in chronic disease. Brain Behav Immun 25: 811-816. doi: 10.1016/j.bbi.2011.02.010
[57]	Brandt C, Pedersen BK (2010) The role of exercise-induced myokines in muscle homeostasis and the defence against chronic diseases. J Biomed Biotechnol 2010: 1-6. doi: 10.1155/2010/520258
[58]	Narici MV, Maffulli N (2010) Sarcopenia: Characteristics, mechanisms and functional significance. Br Med Bull 95: 139-159. doi: 10.1093/bmb/ldq008
[59]	Leeuwenburgh C (2003) Role of apoptosis in sarcopenia. J Gerontol A Biol Sci Med Sci 58: M999-M1001. doi: 10.1093/gerona/58.11.M999
[60]	Demontis F, Rosanna P, Goldberg AL, et al. (2013) Mechanisms of skeletal muscle aging: Insights from Drosophila and mammalian models. Dis Models Mech 6: 1339-1352. doi: 10.1242/dmm.012559
[61]	Walrand S, Guillet C, Salles J, et al. (2011) Physiopathological mechanism of sarcopenia. Clin Geriatr Med 27: 365-385. doi: 10.1016/j.cger.2011.03.005
[62]	Barnes PJ (2006) Theophylline for COPD. Thorax 61: 742-744. doi: 10.1136/thx.2006.061002
[63]	Culpitt SV, de Matos C, Russell RE, et al. (2002) Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 165: 1371-1376. doi: 10.1164/rccm.2105106
[64]	Neuner P, Klosner G, Schauer E, et al. (1994) Pentoxyfylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and TNF alpha by human peripheral blood mononuclear cells. Immunology 83: 262-267.
[65]	Mascali JJ, Cvietusa P, Negri J, et al. (1996) Anti-inflammatory effects of theophylline: Modulation of cytokine production. Ann Allergy Asthma Immunol 77: 34-38. doi: 10.1016/S1081-1206(10)63476-X
[66]	Ito K, Lim S, Caramori G, et al. (2002) A molecular mechanism of the action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 99: 8921-8926. doi: 10.1073/pnas.132556899
[67]	Ichiyami T, Hasegawa S, Matsubara T, et al. (2001) Theophylline inhibits NF-kappa activation and I kappa B alpha degradation in human pulmonary epithelial cells. Naunyn-Schmiedeberg's Arch Pharmacol 364: 558-561. doi: 10.1007/s00210-001-0494-x
[68]	Spatafora M, Chiappara G, Merendino AM, et al. (1994) Theophylline suppresses the release of TNF alpha by blood monocytes and alveolar macrophages. Eur Respir J 7: 223-228. doi: 10.1183/09031936.94.07020223
[69]	Yoshimura T, Usami E, Kurita C, et al. (1995) Effect of theophylline on the production of IL-1 beta, TNF alpha and IL-8 by human peripheral blood mononuclear cells. Biol Pharm Bull 18: 1405-1408. doi: 10.1248/bpb.18.1405
[70]	Subramanian V, Ragulan AB, Jindal A, et al. (2015) The study of tolerability and safety of theophylline given along with formoterol plus budesonide in COPD. J Clin Diagn Res 9: 10-13.
[71]	Hancock REW, Nijnik A, Philpott DJ (2012) Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10: 243-254. doi: 10.1038/nrmicro2745
[72]	Shih YN, Chen YT, Seethala R, et al. (2015) Effect of the use of theophylline and sepsis outcomes. Crit Care Med 43: 274. doi: 10.1097/01.ccm.0000474919.64656.12
[73]	Zhang J, Feng MX, Qu JM (2012) Low dose theophylline showed an inhibitory effect on the production of IL-6 and IL-8 in primary lung fibroblasts from patients with COPD. Mediators Inflammation 2012: 1-7.
[74]	Mosire K, Renvall MJ, Ramsdell JW, et al. (1966) The effect of theophylline on metabolic rate in COPD patients. J Am Coll Nutr 15: 403-407. doi: 10.1080/07315724.1996.10718616
[75]	Cosio BG, Iglesias A, Rios A, et al. (2009) Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 64: 424-429. doi: 10.1136/thx.2008.103432
[76]	Horby P, Lim WS, Emberson J, et al. (2020) Effect of dexamethasone in hospitalized patients with Covid-19: preliminary report. MedRxiv. In press.
[77]	Bodera P, Stankiewicz W (2011) Immunomodulatory properties of thalidomide analogs: Pomalidomide and lenalidomide, experimental and therapeutic applications. Recent Pat Endocr Metab Immune Drug Discovery 5: 192-196. doi: 10.2174/187221411797265890
[78]	Eski M, Sahin I, Sengezer M, et al. (2008) Thalidomide decreases the plasma levels of IL-1 and TNF following burn injury: Is it the new drug for modulation of systemic inflammatory response. Burns 34: 104-108. doi: 10.1016/j.burns.2007.01.007
[79]	Lee SY, Kim W, Park HW, et al. (2015) Anti-sarcopenic effects of diamino-diphenyl sulfone observed in elderly female leprosy survivors: A cross-sectional study. J Cachexia Sarcopenia Muscle 7: 322-329. doi: 10.1002/jcsm.12074
[80]	Borne B, Dijkmans BAC, Rooij HH, et al. (1997) Chloroquine and hydroxychloroquine equally affect TNF alpha, IL-6 and IF gamma production by peripheral blood mononuclear cells. J Rheumatol 24: 55-60.
[81]	Allen SC, Tiwari D (2019) The potential to use chloroquine and other 4-aminoquinoline analogues to modulate persisting inflammation in old age. SM Gerontol Geriatric Res 3: 1020-1024. doi: 10.36876/smggr.1020
[82]	Landi F, Marzetti E, Liperoti R, et al. (2013) Nonsteroidal anti-inflammatory drug (NSAID) use and sarcopenia in older people: Results from the ilSIRENTE study. J Am Med Dir Assoc 14: 626.e9-e13. doi: 10.1016/j.jamda.2013.04.012
[83]	Wu K, Tian S, Zhou H, et al. (2013) Statins protect human endothelial cells from TNF-induced inflammation via ERK5 activation. Biochem Pharmacol 85: 1753-1760. doi: 10.1016/j.bcp.2013.04.009
[84]	Saisho Y (2015) Metformin and inflammation: Its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 15: 196-205. doi: 10.2174/1871530315666150316124019
[85]	Hattori Y, Hattori K, Hayashi T (2015) Pleiotropic benefits of metformin: Macrophage targeting its anti-inflammatory mechanisms. Diabetes 64: 1907-1909. doi: 10.2337/db15-0090

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