Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  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):273–278

    Article  PubMed  Google Scholar 

  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):R186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):305–314

    Article  CAS  Google Scholar 

  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):106–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):301–306

    Article  PubMed  Google Scholar 

  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):156

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):1179–1184

    Article  CAS  Google Scholar 

  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):14–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):112–117

    Article  CAS  Google Scholar 

  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):1824–1833

    Article  CAS  PubMed  Google Scholar 

  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):32–37

    Article  CAS  PubMed  Google Scholar 

  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):585–590

    CAS  PubMed  Google Scholar 

  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):1311–1315

    Article  CAS  Google Scholar 

  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):216–224

    Article  CAS  PubMed  Google Scholar 

  15. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M (2010) Sleep loss and inflammation. Best Pract Res Cl En 24(5):775–784

    Article  CAS  Google Scholar 

  16. Okifuji A, Hare BD (2015) The association between chronic pain and obesity. J Pain Res 8:399–408

    Article  PubMed  PubMed Central  Google Scholar 

  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):169–181

    Article  PubMed  Google Scholar 

  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):135–154

    Article  PubMed  Google Scholar 

  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):154–157

    Google Scholar 

  20. Opp MR (2005) Cytokines and sleep. Sleep Med Rev 9(5):355–364

    Article  PubMed  Google Scholar 

  21. Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1145–1152

    Article  PubMed  PubMed Central  Google Scholar 

  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):135–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):744–759

    Article  CAS  Google Scholar 

  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):141–144

    Article  CAS  Google Scholar 

  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):2545–2550

    Article  PubMed  Google Scholar 

  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):737–740

    Article  PubMed  Google Scholar 

  28. Carpenter JS, Andrykowski MA (1998) Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 45(1):5–13

    Article  CAS  PubMed  Google Scholar 

  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):1495–1507

    Article  PubMed  Google Scholar 

  30. Linton SJ (2000) A review of psychological risk factors in back and neck pain. Spine (Phila Pa 1976) 25(9):1148–1156

    Article  CAS  Google Scholar 

  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):655–661

    Google Scholar 

  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):E109–120

    Article  Google Scholar 

  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–W570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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:b2393

    Article  PubMed  PubMed Central  Google Scholar 

  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):1092–1101

    Article  PubMed  Google Scholar 

  36. Clyne B, Olshaker JS (1999) The C-reactive protein. J Emerg Med 17(6):1019–1025

    Article  CAS  PubMed  Google Scholar 

  37. Sarma JV, Ward PA (2011) The complement system. Cell Tissue Res 343(1):227–235

    Article  CAS  PubMed  Google Scholar 

  38. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6):a001651

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):367–374

    Article  CAS  PubMed  Google Scholar 

  40. Wu Y, Potempa LA, El Kebir D, Filep JG (2015) C-reactive protein and inflammation: conformational changes affect function. Biol Chem 396(11):1181–1197

    Article  CAS  PubMed  Google Scholar 

  41. Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38(2–3):189–197

    Article  CAS  PubMed  Google Scholar 

  42. Ansar W, Ghosh S (2013) C-reactive protein and the biology of disease. Immunol Res 56(1):131–142

    Article  CAS  PubMed  Google Scholar 

  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. 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 8:14188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 60:84–92

    Article  PubMed  Google Scholar 

  46. Pritchett JW (1996) C-reactive protein levels determine the severity of soft-tissue injuries. Am J Orthop (Belle Mead NJ) 25(11):759–761

    CAS  Google Scholar 

  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):149–153

    Article  CAS  PubMed  Google Scholar 

  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):295–299

    PubMed  Google Scholar 

  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):1151–1154

    Article  CAS  PubMed  Google Scholar 

  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):218–224

    Article  CAS  Google Scholar 

  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):1974–1982

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Risbud MV, Shapiro IM (2014) Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10(1):44–56

    Article  CAS  PubMed  Google Scholar 

  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):259–262

    Article  PubMed  Google Scholar 

  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):442–450

    Article  CAS  PubMed  Google Scholar 

  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):401–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):508–510

    Article  CAS  PubMed  Google Scholar 

  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):1361–1363

    Article  CAS  PubMed  Google Scholar 

  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):1366–1370

    Article  CAS  PubMed  Google Scholar 

  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):647–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kalliolias GD, Ivashkiv LB (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12(1):49–62

    Article  CAS  PubMed  Google Scholar 

  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):1–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. McDermott MF (2001) TNF and TNFR biology in health and disease. Cell Mol Biol 47(4):619–635

    CAS  PubMed  Google Scholar 

  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):599–609

    Article  PubMed  CAS  Google Scholar 

  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):1308–1318

    Article  CAS  PubMed  Google Scholar 

  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):3806–3814

    Article  CAS  PubMed  Google Scholar 

  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):2368–2378

    Article  CAS  PubMed  Google Scholar 

  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):4015–4023

    Article  PubMed  Google Scholar 

  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):3731–3736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):757–771

    Article  PubMed  PubMed Central  Google Scholar 

  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):419–427

    Article  CAS  PubMed  Google Scholar 

  71. Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6(7):521–532

    Article  CAS  PubMed  Google Scholar 

  72. McMahon SB, Cafferty WBJ, Marchand F (2005) Immune and glial cell factors as pain mediators and modulators. Exp Neurol 192(2):444–462

    Article  CAS  PubMed  Google Scholar 

  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):311–318

    Article  PubMed  Google Scholar 

  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):415–420

    Article  PubMed  Google Scholar 

  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):953–963

    Article  PubMed  PubMed Central  Google Scholar 

  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):9060–9068

    Article  CAS  Google Scholar 

  77. Friedman EM, Herd P (2010) Income, education, and inflammation: differential associations in a national probability sample (The MIDUS Study). Psychosom Med 72(3):290–300

    Article  PubMed  PubMed Central  Google Scholar 

  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):171–186

    Article  CAS  PubMed  Google Scholar 

  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):e1005973

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):339–342

    Article  CAS  PubMed  Google Scholar 

  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):9589–9594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):878–888

    CAS  Google Scholar 

  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):1097–1101

    CAS  PubMed  PubMed Central  Google Scholar 

  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):113–118

    CAS  PubMed  Google Scholar 

  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):40–47

    CAS  PubMed  Google Scholar 

  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):3517–3523

    CAS  PubMed  Google Scholar 

  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):1390–1397

    Article  CAS  PubMed  Google Scholar 

  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–U1365

    Article  CAS  PubMed  Google Scholar 

  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):311–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):165–173

    Article  CAS  Google Scholar 

  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):318–324

    Article  CAS  PubMed  Google Scholar 

  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):40–52

    Article  PubMed  Google Scholar 

  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):1756–1762

    Article  CAS  PubMed  Google Scholar 

  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):131–140

    Article  CAS  Google Scholar 

  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):2603–2607

    Article  CAS  PubMed  Google Scholar 

  96. Irwin MR, Cole SW (2011) Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11(9):625–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):774–815

    Article  PubMed  PubMed Central  Google Scholar 

  98. Hogan D, Morrow JD, Smith EM, Opp MR (2003) Interleukin-6 alters sleep of rats. J Neuroimmunol 137(1–2):59–66

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 193:39–47

    Article  PubMed  PubMed Central  Google Scholar 

  101. Rohleder N, Aringer M, Boentert M (2012) Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci 1261:88–96

    Article  CAS  PubMed  Google Scholar 

  102. Davis CJ, Krueger JM (2012) Sleep and cytokines. Sleep Med Clin 7(3):517–527

    Article  PubMed  PubMed Central  Google Scholar 

  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):1313–1316

    Article  CAS  PubMed  Google Scholar 

  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 53:139–159

    Article  CAS  Google Scholar 

  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):429–433

    Article  CAS  PubMed  Google Scholar 

  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):230–239

    Article  CAS  PubMed  Google Scholar 

  107. Blackburn-Munro G, Blackburn-Munro RE (2001) Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 13(12):1009–1023

    Article  CAS  PubMed  Google Scholar 

  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):168–179

    Article  CAS  Google Scholar 

  109. Mirescu C, Gould E (2006) Stress and adult neurogenesis. Hippocampus 16(3):233–238

    Article  CAS  PubMed  Google Scholar 

  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):1554–1565

    Article  PubMed  Google Scholar 

  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):79–133

    Article  CAS  PubMed  Google Scholar 

  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):519–531

    Article  CAS  PubMed  Google Scholar 

  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):79–128

    Article  CAS  PubMed  Google Scholar 

  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):1209–1216

    Article  CAS  PubMed  Google Scholar 

  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 12:114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130(2):226–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1216–1225

    Article  CAS  PubMed  Google Scholar 

  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):1871–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):112–124

    Article  CAS  PubMed  Google Scholar 

  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):70–77

    Article  CAS  PubMed  Google Scholar 

  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):113–122

    Article  CAS  PubMed  Google Scholar 

  122. Strouse TB (2007) The Relationship between cytokines and pain/depression. Curr Pain Headache Rep 11(2):98–103

    Article  PubMed  Google Scholar 

  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):247–260

    Article  Google Scholar 

  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):171–179

    Article  PubMed  Google Scholar 

  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):257–267

    Article  PubMed  Google Scholar 

  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):110–112

    Article  CAS  Google Scholar 

  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):326–331

    Article  PubMed  Google Scholar 

  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):2030–2040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):511–522

    Article  CAS  Google Scholar 

  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):419–426

    Article  CAS  PubMed  Google Scholar 

  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):1068–1076

    Article  PubMed  Google Scholar 

  132. Petrovsky N, McNair P, Harrison LC (1998) Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications. Cytokine 10(4):307–312

    Article  CAS  PubMed  Google Scholar 

  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):444–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):426–430

    CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by the National Health and Medical Research Council (NHMRC) of Australia (Program Grant: ID631717; Project Grant ID631369). PWH supported by NHMRC Fellowship ID1002190. The manuscript submitted does not contain information about medical device(s)/drug(s).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul W. Hodges.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 417 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klyne, D.M., Barbe, M.F., van den Hoorn, W. et al. 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. Eur Spine J 27, 763–777 (2018). https://doi.org/10.1007/s00586-018-5490-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-018-5490-7

Keywords

Navigation