European Spine Journal

, Volume 27, Issue 4, pp 763–777 | Cite as

ISSLS PRIZE IN CLINICAL SCIENCE 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode—the good, the bad, and the ugly

  • David M. Klyne
  • Mary F. Barbe
  • Wolbert van den Hoorn
  • Paul W. Hodges
Original Article
First Online:
Received:
Accepted:

Abstract

Study design

Prospective longitudinal study.

Objective

To determine whether systemic cytokines and C-reactive protein (CRP) during an acute episode of low back pain (LBP) differ between individuals who did and did not recover by 6 months and to identify sub-groups based on patterns of inflammatory, psychological, and sleep features associated with recovery/non-recovery.

Summary of background data

Systemic inflammation is observed in chronic LBP and may contribute to the transition from acute to persistent LBP. Longitudinal studies are required to determine whether changes present early or develop over time. Psychological and/or sleep-related factors may be related.

Methods

Individuals within 2 weeks of onset of acute LBP (N = 109) and pain-free controls (N = 55) provided blood for assessment of CRP, tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1β, and completed questionnaires related to pain, disability, sleep, and psychological status. LBP participants repeated measurements at 6 months. Biomarkers were compared between LBP and control participants at baseline, and in longitudinal (baseline/6 months) analysis, between unrecovered (≥pain and disability), partially recovered (reduced pain and/or disability) and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of inflammatory, psychological, sleep, and pain data using hierarchical clustering and related the clusters to recovery (% change in pain) at 6 months.

Results

CRP was higher in acute LBP than controls at baseline. In LBP, baseline CRP was higher in the recovered than non-recovered groups. Conversely, TNF was higher at both time-points in the non-recovered than recovered groups. Two sub-groups were identified that associated with more (“inflammatory/poor sleep”) or less (“high TNF/depression”) recovery.

Conclusions

This is the first evidence of a relationship between an “acute-phase” systemic inflammatory response and recovery at 6 months. High inflammation (CRP/IL-6) was associated with good recovery, but specific elevation of TNF, along with depressive symptoms, was associated with bad recovery. Depression and TNF may have a two-way relationship.

Graphical abstract

These slides can be retrieved under Electronic Supplementary Material.

Keywords

Pro-inflammatory cytokines C-reactive protein (CRP) Tumor necrosis factor (TNF) Interleukin-6 (IL-6) Interleukin-1β (IL-1β) Systemic Depression Sleep Low back pain (LBP) Longitudinal Transition to chronicity 
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Notes

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest related to this work.

Ethical approval

Approved by The University of Queensland Institutional Medical Research Ethics Committee.

Supplementary material

586_2018_5490_MOESM1_ESM.pptx (418 kb)
Supplementary material 1 (PPTX 417 kb)

References

  1. 1.
    Wang H, Schiltenwolf M, Buchner M (2008) The role of TNF-alpha in patients with chronic low back pain-a prospective comparative longitudinal study. Clin J Pain 24(3):273–278PubMedCrossRefGoogle Scholar
  2. 2.
    Wang H, Ahrens C, Rief W, Gantz S, Schiltenwolf M, Richter W (2010) Influence of depression symptoms on serum tumor necrosis factor-alpha of patients with chronic low back pain. Arthritis Res Ther 12(5):R186PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Carp SJ, Barbe MF, Winter KA, Amin M, Barr AE (2007) Inflammatory biomarkers increase with severity of upper-extremity overuse disorders. Clin Sci (Lond) 112(5):305–314CrossRefGoogle Scholar
  4. 4.
    Parkitny L, McAuley JH, Di Pietro F, Stanton TR, O’Connell NE, Marinus J, van Hilten JJ, Moseley GL (2013) Inflammation in complex regional pain syndrome A systematic review and meta-analysis. Neurology 80(1):106–117PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Della Vedova C, Cathcart S, Dohnalek A, Lee V, Hutchinson MR, Immink MA, Hayball J (2013) Peripheral interleukin-1B levels are elevated in chronic tension-type headache patients. Pain Res Manag 18(6):301–306PubMedCrossRefGoogle Scholar
  6. 6.
    Hernandez ME, Becerril E, Perez M, Leff P, Anton B, Estrada S, Estrada I, Sarasa M, Serrano E, Pavon L (2010) Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index. BMC Res Notes 3(1):156PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Shimura Y, Kurosawa H, Sugawara Y, Tsuchiya M, Sawa M, Kaneko H, Futami I, Liu L, Sadatsuki R, Hada S, Iwase Y, Kaneko K, Ishijima M (2013) The factors associated with pain severity in patients with knee osteoarthritis vary according to the radiographic disease severity: a cross-sectional study. Osteoarthr Cartilage 21(9):1179–1184CrossRefGoogle Scholar
  8. 8.
    Asanuma Y, Oeser A, Stanley E, Bailey DG, Shintani A, Stein CM (2008) Effects of C-reactive protein and homocysteine on cytokine production: modulation by pravastatin. Arch Drug Inf 1(1):14–22PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Moshage HJ, Roelofs HMJ, Vanpelt JF, Hazenberg BPC, Vanleeuwen MA, Limburg PC, Aarden LA, Yap SH (1988) The effect of interleukin-1, interleukin-6 and its interrelationship on the synthesis of serum amyloid a-reactive and C-reactive protein in primary cultures of adult human hepatocytes. Biochem Bioph Res Co 155(1):112–117CrossRefGoogle Scholar
  10. 10.
    Anty R, Bekri S, Luciani N, Saint-Paul MC, Dahman M, Iannelli A, Ben Amor I, Staccini-Myx A, Huet PM, Gugenheim J, Sadoul JL, Le Marchand-Brustel Y, Tran A, Gual P (2006) The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, type 2 diabetes, and NASH. Am J Gastroenterol 101(8):1824–1833PubMedCrossRefGoogle Scholar
  11. 11.
    Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, Wolf A, Freynhagen R (2007) Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res 56(1):32–37PubMedCrossRefGoogle Scholar
  12. 12.
    Mukai E, Nagashima M, Hirano D, Yoshino S (2000) Comparative study of symptoms and neuroendocrine-immune network mediator levels between rheumatoid arthritis patients and healthy subjects. Clin Exp Rheumatol 18(5):585–590PubMedGoogle Scholar
  13. 13.
    Rannou F, Ouanes W, Boutron I, Lovisi B, Fayad F, Mace Y, Borderie D, Guerini H, Poiraudeau S, Revel M (2007) High-sensitivity C-reactive protein in chronic low pack pain with vertebral end-plate modic signal changes. Arthrit Rheum-Arthr 57(7):1311–1315CrossRefGoogle Scholar
  14. 14.
    Edwards RR, Calahan C, Mensing G, Smith M, Haythornthwaite JA (2011) Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol 7(4):216–224PubMedCrossRefGoogle Scholar
  15. 15.
    Mullington JM, Simpson NS, Meier-Ewert HK, Haack M (2010) Sleep loss and inflammation. Best Pract Res Cl En 24(5):775–784CrossRefGoogle Scholar
  16. 16.
    Okifuji A, Hare BD (2015) The association between chronic pain and obesity. J Pain Res 8:399–408PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kelly GA, Blake C, Power CK, O’Keeffe D, Fullen BM (2011) The association between chronic low back pain and sleep a systematic review. Clin J Pain 27(2):169–181PubMedCrossRefGoogle Scholar
  18. 18.
    Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, Viikari-Juntura E (2010) The association between obesity and low back pain: a meta-analysis. Am J Epidemiol 171(2):135–154PubMedCrossRefGoogle Scholar
  19. 19.
    Henschke N, Maher CG, Refshauge KM, Herbert RD, Cumming RG, Bleasel J, York J, Das A, McAuley JH (2008) Prognosis in patients with recent onset low back pain in Australian primary care: inception cohort study. Br Med J 337(7662):154–157Google Scholar
  20. 20.
    Opp MR (2005) Cytokines and sleep. Sleep Med Rev 9(5):355–364PubMedCrossRefGoogle Scholar
  21. 21.
    Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Haack M, Sanchez E, Mullington JM (2007) Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 30(9):1145–1152PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, Mcguire L, Page GG (2008) Association of catastrophizing with interleukin-6 responses to acute pain. Pain 140(1):135–144PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M (2011) In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuro-Psychoph 35(3):744–759CrossRefGoogle Scholar
  25. 25.
    Roland M, Morris R (1983) A study of the natural history of back pain. Part I: development of a reliable and sensitive measure of disability in low-back pain. Spine (Phila Pa 1976) 8(2):141–144CrossRefGoogle Scholar
  26. 26.
    Boonstra AM, Schiphorst Preuper HR, Balk GA, Stewart RE (2014) Cut-off points for mild, moderate, and severe pain on the visual analogue scale for pain in patients with chronic musculoskeletal pain. Pain 155(12):2545–2550PubMedCrossRefGoogle Scholar
  27. 27.
    Backhaus J, Junghanns K, Broocks A, Riemann D, Hohagen F (2002) Test–retest reliability and validity of the Pittsburgh Sleep Quality Index in primary insomnia. J Psychosom Res 53(3):737–740PubMedCrossRefGoogle Scholar
  28. 28.
    Carpenter JS, Andrykowski MA (1998) Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 45(1):5–13PubMedCrossRefGoogle Scholar
  29. 29.
    Boersma K, Linton SJ (2005) How does persistent pain develop? An analysis of the relationship between psychological variables, pain and function across stages of chronicity. Behav Res Ther 43(11):1495–1507PubMedCrossRefGoogle Scholar
  30. 30.
    Linton SJ (2000) A review of psychological risk factors in back and neck pain. Spine (Phila Pa 1976) 25(9):1148–1156CrossRefGoogle Scholar
  31. 31.
    Mallen CD, Peat G, Thomas E, Dunn KM, Croft PR (2007) Prognostic factors for musculoskeletal pain in primary care: a systematic review. Brit J Gen Pract 57(541):655–661Google Scholar
  32. 32.
    Pincus T, Burton AK, Vogel S, Field AP (2002) A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine (Phila Pa 1976) 27(5):E109–120CrossRefGoogle Scholar
  33. 33.
    Metsalu T, Vilo J (2015) ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res 43(W1):W566–W570PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, Wood AM, Carpenter JR (2009) Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 338:b2393PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Moons KGM, Donders RART, Stijnen T, Harrell FE (2006) Using the outcome for imputation of missing predictor values was preferred. J Clin Epidemiol 59(10):1092–1101PubMedCrossRefGoogle Scholar
  36. 36.
    Clyne B, Olshaker JS (1999) The C-reactive protein. J Emerg Med 17(6):1019–1025PubMedCrossRefGoogle Scholar
  37. 37.
    Sarma JV, Ward PA (2011) The complement system. Cell Tissue Res 343(1):227–235PubMedCrossRefGoogle Scholar
  38. 38.
    Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6):a001651PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Liu N, Liu JT, Ji YY, Lu PP (2010) C-reactive protein triggers inflammatory responses partly via TLR4/IRF3/NF-kappaB signaling pathway in rat vascular smooth muscle cells. Life Sci 87(11–12):367–374PubMedCrossRefGoogle Scholar
  40. 40.
    Wu Y, Potempa LA, El Kebir D, Filep JG (2015) C-reactive protein and inflammation: conformational changes affect function. Biol Chem 396(11):1181–1197PubMedCrossRefGoogle Scholar
  41. 41.
    Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38(2–3):189–197PubMedCrossRefGoogle Scholar
  42. 42.
    Ansar W, Ghosh S (2013) C-reactive protein and the biology of disease. Immunol Res 56(1):131–142PubMedCrossRefGoogle Scholar
  43. 43.
    Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU (2015) Targeting C-reactive protein in inflammatory disease by preventing conformational changes. Mediators Inflamm 2015.  https://doi.org/10.1155/2015/372432
  44. 44.
    Braig D, Nero TL, Koch HG, Kaiser B, Wang X, Thiele JR, Morton CJ, Zeller J, Kiefer J, Potempa LA, Mellett NA, Miles LA, Du XJ, Meikle PJ, Huber-Lang M, Stark GB, Parker MW, Peter K, Eisenhardt SU (2017) Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nat Commun 8:14188PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Klyne DM, Barbe MF, Hodges PW (2017) Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain. Brain Behav Immun 60:84–92PubMedCrossRefGoogle Scholar
  46. 46.
    Pritchett JW (1996) C-reactive protein levels determine the severity of soft-tissue injuries. Am J Orthop (Belle Mead NJ) 25(11):759–761Google Scholar
  47. 47.
    Rechardt M, Shiri R, Matikainen S, Viikari-Juntura E, Karppinen J, Alenius H (2011) Soluble IL-1RII and IL-18 are associated with incipient upper extremity soft tissue disorders. Cytokine 54(2):149–153PubMedCrossRefGoogle Scholar
  48. 48.
    Ackerman WE 3rd, Zhang JM (2006) Serum hs-CRP as a useful marker for predicting the efficacy of lumbar epidural steroid injections on pain relief in patients with lumbar disc herniations. J Ky Med Assoc 104(7):295–299PubMedGoogle Scholar
  49. 49.
    Sugimori K, Kawaguchi Y, Morita M, Kitajima I, Kimura T (2003) High-sensitivity analysis of serum C-reactive protein in young patients with lumbar disc herniation. J Bone Joint Surg Br 85(8):1151–1154PubMedCrossRefGoogle Scholar
  50. 50.
    Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T (1996) Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (Phila Pa 1976) 21(2):218–224CrossRefGoogle Scholar
  51. 51.
    Shamji MF, Setton LA, Jarvis W, So S, Chen J, Jing L, Bullock R, Isaacs RE, Brown C, Richardson WJ (2010) Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum 62(7):1974–1982PubMedPubMedCentralGoogle Scholar
  52. 52.
    Risbud MV, Shapiro IM (2014) Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10(1):44–56PubMedCrossRefGoogle Scholar
  53. 53.
    Kraychete DC, Sakata RK, Issy AM, Bacellar O, Santos-Jesus R, Carvalho EM (2010) Serum cytokine levels in patients with chronic low back pain due to herniated disc: analytical cross-sectional study. Sao Paulo Med J 128(5):259–262PubMedCrossRefGoogle Scholar
  54. 54.
    Gillett A, Marta M, Jin T, Tuncel J, Leclerc P, Nohra R, Lange S, Holmdahl R, Olsson T, Harris RA, Jagodic M (2010) TNF production in macrophages is genetically determined and regulates inflammatory disease in rats. J Immunol 185(1):442–450PubMedCrossRefGoogle Scholar
  55. 55.
    Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S, Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113(3):401–406PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371(6497):508–510PubMedCrossRefGoogle Scholar
  57. 57.
    Fernandez-Arquero M, Arroyo R, Rubio A, Martin C, Vigil P, Conejero L, Figueredo MA, de la Concha EG (1999) Primary association of a TNF gene polymorphism with susceptibility to multiple sclerosis. Neurology 53(6):1361–1363PubMedCrossRefGoogle Scholar
  58. 58.
    Martinez A, Fernandez-Arquero M, Pascual-Salcedo D, Conejero L, Alves H, Balsa A, de la Concha EG (2000) Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum 43(6):1366–1370PubMedCrossRefGoogle Scholar
  59. 59.
    Biffl WL, Moore EE, Moore FA, Peterson VM (1996) Interleukin-6 in the injured patient marker of injury or mediator of inflammation? Ann Surg 224(5):647–664PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kalliolias GD, Ivashkiv LB (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12(1):49–62PubMedCrossRefGoogle Scholar
  61. 61.
    Hehlgans T, Pfeffer K (2005) The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 115(1):1–20PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    McDermott MF (2001) TNF and TNFR biology in health and disease. Cell Mol Biol 47(4):619–635PubMedGoogle Scholar
  63. 63.
    Konig C, Zharsky M, Moller C, Schaible HG, Ebersberger A (2014) Involvement of peripheral and spinal tumor necrosis factor alpha in spinal cord hyperexcitability during knee joint inflammation in rats. Arthritis Rheumatol 66(3):599–609PubMedCrossRefGoogle Scholar
  64. 64.
    Boettger MK, Weber K, Grossmann D, Gajda M, Bauer R, Bar KJ, Schulz S, Voss A, Geis C, Brauer R, Schaible HG (2010) Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum 62(5):1308–1318PubMedCrossRefGoogle Scholar
  65. 65.
    Richter F, Natura G, Loser S, Schmidt K, Viisanen H, Schaible HG (2010) Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum 62(12):3806–3814PubMedCrossRefGoogle Scholar
  66. 66.
    Boettger MK, Hensellek S, Richter F, Gajda M, Stockigt R, von Banchet GS, Brauer R, Schaible HG (2008) Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis. Arthritis Rheum 58(8):2368–2378PubMedCrossRefGoogle Scholar
  67. 67.
    Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R (2007) Collagen-induced arthritis as a model of hyperalgesia. Arthritis Rheum 56(12):4015–4023PubMedCrossRefGoogle Scholar
  68. 68.
    Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA 108(9):3731–3736PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Andrade P, Visser-Vandewalle V, Hoffmann C, Steinbusch HW, Daemen MA, Hoogland G (2011) Role of TNF-alpha during central sensitization in preclinical studies. Neurol Sci 32(5):757–771PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR (2011) TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152(2):419–427PubMedCrossRefGoogle Scholar
  71. 71.
    Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6(7):521–532PubMedCrossRefGoogle Scholar
  72. 72.
    McMahon SB, Cafferty WBJ, Marchand F (2005) Immune and glial cell factors as pain mediators and modulators. Exp Neurol 192(2):444–462PubMedCrossRefGoogle Scholar
  73. 73.
    O’Sullivan P, Waller R, Wright A, Gardner J, Johnston R, Payne C, Shannon A, Ware B, Smith A (2014) Sensory characteristics of chronic non-specific low back pain: a subgroup investigation. Man Ther 19(4):311–318PubMedCrossRefGoogle Scholar
  74. 74.
    O’Neill S, Manniche C, Graven-Nielsen T, Arendt-Nielsen L (2007) Generalized deep-tissue hyperalgesia in patients with chronic low-back pain. Eur J Pain 11(4):415–420PubMedCrossRefGoogle Scholar
  75. 75.
    Edwards RR, Wasan AD, Michna E, Greenbaum S, Ross E, Jamison RN (2011) Elevated pain sensitivity in chronic pain patients at risk for opioid misuse. J Pain 12(9):953–963PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Li SP, Goldman ND (1996) Regulation of human C-reactive protein gene expression by two synergistic IL-6 responsive elements. Biochemistry-Us 35(28):9060–9068CrossRefGoogle Scholar
  77. 77.
    Friedman EM, Herd P (2010) Income, education, and inflammation: differential associations in a national probability sample (The MIDUS Study). Psychosom Med 72(3):290–300PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71(2):171–186PubMedCrossRefGoogle Scholar
  79. 79.
    Slaats J, ten Oever J, van de Veerdonk FL, Netea MG (2016) IL-1β/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. Plos Pathog 12(12):e1005973PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Kohler G (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368(6469):339–342PubMedCrossRefGoogle Scholar
  81. 81.
    McLoughlin RM, Jenkins BJ, Grail D, Williams AS, Fielding CA, Parker CR, Ernst M, Topley N, Jones SA (2005) IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci USA 102(27):9589–9594PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. BBA-Mol Cell Res 1813(5):878–888Google Scholar
  83. 83.
    Ulich TR, Yin SM, Guo KZ, Yi EHS, Remick D, Delcastillo J (1991) Intratracheal injection of endotoxin and cytokines. 2. interleukin-6 and transforming growth-factor-beta inhibit acute-inflammation. Am J Pathol 138(5):1097–1101PubMedPubMedCentralGoogle Scholar
  84. 84.
    Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (Il-6) as an antiinflammatory cytokine—induction of circulating Il-1-receptor antagonist and soluble tumor-necrosis-factor receptor-P55. Blood 83(1):113–118PubMedGoogle Scholar
  85. 85.
    Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA (1990) Correlations and interactions in the production of interleukin-6 (Il-6), Il-1, and tumor necrosis factor (Tnf) in human-blood mononuclear-cells—Il-6 suppresses Il-1 and TNF. Blood 75(1):40–47PubMedGoogle Scholar
  86. 86.
    Aderka D, Le JM, Vilcek J (1989) Il-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human-monocytes, U937 cells, and in mice. J Immunol 143(11):3517–3523PubMedGoogle Scholar
  87. 87.
    McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397PubMedCrossRefGoogle Scholar
  88. 88.
    Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJM, O’Shea JJ, Hunter CA (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8(12):1363–U1365PubMedCrossRefGoogle Scholar
  89. 89.
    Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101(2):311–320PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Adser H, Wojtaszewski JFP, Jakobsen AH, Kiilerich K, Hidalgo J, Pilegaard H (2011) Interleukin-6 modifies mRNA expression in mouse skeletal muscle. Acta Physiol 202(2):165–173CrossRefGoogle Scholar
  91. 91.
    Chennaoui M, Sauvet F, Drogou C, Van Beers P, Langrume C, Guillard M, Gourby B, Bourrilhon C, Florence G, Gomez-Merino D (2011) Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-alpha) levels in healthy men. Cytokine 56(2):318–324PubMedCrossRefGoogle Scholar
  92. 92.
    Irwin MR, Olmstead R, Carroll JE (2016) Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiat 80(1):40–52PubMedCrossRefGoogle Scholar
  93. 93.
    Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S (2006) Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 166(16):1756–1762PubMedCrossRefGoogle Scholar
  94. 94.
    Vgontzas AN, Bixler EO, Lin HM, Prolo P, Trakada G, Chrousos GP (2005) IL-6 and its circadian secretion in humans. Neuroimmunomodulat 12(3):131–140CrossRefGoogle Scholar
  95. 95.
    Vgontzas AN, Papanicolaou DA, Bixler EO, Lotsikas A, Zachman K, Kales A, Prolo P, Wong ML, Licinio J, Gold PW, Hermida RC, Mastorakos G, Chrousos GP (1999) Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 84(8):2603–2607PubMedCrossRefGoogle Scholar
  96. 96.
    Irwin MR, Cole SW (2011) Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11(9):625–632PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Slavich GM, Irwin MR (2014) From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 140(3):774–815PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hogan D, Morrow JD, Smith EM, Opp MR (2003) Interleukin-6 alters sleep of rats. J Neuroimmunol 137(1–2):59–66PubMedCrossRefGoogle Scholar
  99. 99.
    Hurtado-Alvarado G, Pavon L, Castillo-Garcia SA, Hernandez ME, Dominguez-Salazar E, Velazquez-Moctezuma J, Gomez-Gonzalez B (2013) Sleep loss as a factor to induce cellular and molecular inflammatory variations. Clin Dev Immunol 2013:801341.  https://doi.org/10.1155/2013/801341 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Krueger JM, Clinton JM, Winters BD, Zielinski MR, Taishi P, Jewett KA, Davis CJ (2011) Involvement of cytokines in slow wave sleep. Prog Brain Res 193:39–47PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Rohleder N, Aringer M, Boentert M (2012) Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci 1261:88–96PubMedCrossRefGoogle Scholar
  102. 102.
    Davis CJ, Krueger JM (2012) Sleep and cytokines. Sleep Med Clin 7(3):517–527PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 82(5):1313–1316PubMedCrossRefGoogle Scholar
  104. 104.
    Fasick V, Spengler RN, Samankan S, Nader ND, Ignatowski TA (2015) The hippocampus and TNF: common links between chronic pain and depression. Neurosci Biobehav R 53:139–159CrossRefGoogle Scholar
  105. 105.
    Tuglu C, Kara SH, Caliyurt O, Vardar E, Abay E (2003) Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology 170(4):429–433PubMedCrossRefGoogle Scholar
  106. 106.
    Liu Y, Ho RC, Mak A (2012) Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 139(3):230–239PubMedCrossRefGoogle Scholar
  107. 107.
    Blackburn-Munro G, Blackburn-Munro RE (2001) Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 13(12):1009–1023PubMedCrossRefGoogle Scholar
  108. 108.
    de Kloet ER, DeRijk RH, Meijer OC (2007) Therapy insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression? Nat Clin Pract Endoc 3(2):168–179CrossRefGoogle Scholar
  109. 109.
    Mirescu C, Gould E (2006) Stress and adult neurogenesis. Hippocampus 16(3):233–238PubMedCrossRefGoogle Scholar
  110. 110.
    Raison CL, Miller AH (2003) When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 160(9):1554–1565PubMedCrossRefGoogle Scholar
  111. 111.
    McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM (1997) The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Rev 23(1–2):79–133PubMedCrossRefGoogle Scholar
  112. 112.
    Reynolds JL, Ignatowski TA, Sud R, Spengler RN (2005) An antidepressant mechanism of desipramine is to decrease tumor necrosis factor-alpha production culminating in increases in noradrenergic neurotransmission. Neuroscience 133(2):519–531PubMedCrossRefGoogle Scholar
  113. 113.
    Harro J, Oreland L (2001) Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus. Brain Res Rev 38(1–2):79–128PubMedCrossRefGoogle Scholar
  114. 114.
    Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63(11):1209–1216PubMedCrossRefGoogle Scholar
  115. 115.
    Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 12:114PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130(2):226–238PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Reynolds JL, Ignatowski TA, Sud R, Spengler RN (2004) Brain-derived tumor necrosis factor-alpha and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant. J Pharmacol Exp Ther 310(3):1216–1225PubMedCrossRefGoogle Scholar
  118. 118.
    Martuscello RT, Spengler RN, Bonoiu AC, Davidson BA, Helinski J, Ding H, Mahajan S, Kumar R, Bergey EJ, Knight PR, Prasad PN, Ignatowski TA (2012) Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. Pain 153(9):1871–1882PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Sud R, Ignatowski TA, Lo CP, Spengler RN (2007) Uncovering molecular elements of brain-body communication during development and treatment of neuropathic pain. Brain Behav Immun 21(1):112–124PubMedCrossRefGoogle Scholar
  120. 120.
    Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN (1999) Brain-derived TNFalpha mediates neuropathic pain. Brain Res 841(1–2):70–77PubMedCrossRefGoogle Scholar
  121. 121.
    Covey WC, Ignatowski TA, Knight PR, Spengler RN (2000) Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res 859(1):113–122PubMedCrossRefGoogle Scholar
  122. 122.
    Strouse TB (2007) The Relationship between cytokines and pain/depression. Curr Pain Headache Rep 11(2):98–103PubMedCrossRefGoogle Scholar
  123. 123.
    Darnall BD, Aickin M, Zwickey H (2010) pilot study of inflammatory responses following a negative imaginal focus in persons with chronic pain: analysis by sex/gender. Gender Med 7(3):247–260CrossRefGoogle Scholar
  124. 124.
    Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, Evoniuk G, Jansen W, Leon AC, Minkwitz M, Pikalov A, Stassen HH, Szegedi A, Tohen M, Van Willigenburg AP, Calabrese JR (2011) Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord 130(1–2):171–179PubMedCrossRefGoogle Scholar
  125. 125.
    Katz MM, Koslow SH, Frazer A (1996) Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs. Depress Anxiety 4(6):257–267PubMedCrossRefGoogle Scholar
  126. 126.
    Katz MM, Bowden C, Stokes P, Casper R, Frazer A, Koslow SH, Kocsis J, Secunda S, Swann A, Berman N (1997) Can the effects of antidepressants be observed in the first two weeks of treatment? Neuropsychopharmacol 17(2):110–112CrossRefGoogle Scholar
  127. 127.
    O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007) Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41(3–4):326–331PubMedCrossRefGoogle Scholar
  128. 128.
    Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J (2007) Neurobiology of depression: an integrated view of key findings. Int J Clin Pract 61(12):2030–2040PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatr 14(5):511–522CrossRefGoogle Scholar
  130. 130.
    Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL (2012) Depressive-like behavior induced by tumor necrosis factor-alpha in mice. Neuropharmacology 62(1):419–426PubMedCrossRefGoogle Scholar
  131. 131.
    Scheff JD, Calvano SE, Lowry SF, Androulakis IP (2010) Modeling the influence of circadian rhythms on the acute inflammatory response. J Theor Biol 264(3):1068–1076PubMedCrossRefGoogle Scholar
  132. 132.
    Petrovsky N, McNair P, Harrison LC (1998) Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications. Cytokine 10(4):307–312PubMedCrossRefGoogle Scholar
  133. 133.
    Sitton NG, Taggart AJ, Dixon JS, Surrall KE, Bird HA (1984) Circadian variation in biochemical assessments used to monitor rheumatoid-arthritis. Ann Rheum Dis 43(3):444–450PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM (2001) Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem 47(3):426–430PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • David M. Klyne
    • 1
  • Mary F. Barbe
    • 2
  • Wolbert van den Hoorn
    • 1
  • Paul W. Hodges
    • 1
  1. 1.NHMRC Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation SciencesThe University of QueenslandBrisbaneAustralia
  2. 2.Department of Anatomy and Cell Biology, Temple University School of MedicineTemple UniversityPhiladelphiaUSA

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