Salivary markers of inflammation in response to acute stress

There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research.

[1]  W. Kuis,et al.  Stress induces increases in IL-6 production by leucocytes of patients with the chronic inflammatory disease juvenile rheumatoid arthritis: a putative role for α1-adrenergic receptors , 2000, Journal of Neuroimmunology.

[2]  Kenta Kimura,et al.  An increase in salivary interleukin-6 level following acute psychosocial stress and its biological correlates in healthy young adults , 2013, Biological Psychology.

[3]  E. Rossomando,et al.  Candidate salivary biomarkers associated with alveolar bone loss: cross-sectional and in vitro studies. , 2007, FEMS immunology and medical microbiology.

[4]  S. Gold,et al.  Endocrine and Cytokine Responses to Acute Psychological Stress in Multiple Sclerosis , 2002, Brain, Behavior, and Immunity.

[5]  A. Steptoe,et al.  Mental stress-induced platelet activation and increases in C-reactive protein concentration in coronary artery disease , 2003 .

[6]  A. Kikukawa,et al.  Salivary chromogranin-A as a marker of psychological stress during a cognitive test battery in humans , 2006, Stress.

[7]  A. Abbas,et al.  Interleukin‐2 in the development and control of inflammatory disease , 2008, Immunological reviews.

[8]  E. Shirtcliff,et al.  Use of salivary biomarkers in biobehavioral research: cotton-based sample collection methods can interfere with salivary immunoassay results , 2001, Psychoneuroendocrinology.

[9]  T. Åkerstedt,et al.  Effects of Sustained Sleep Restriction on Mitogen-Stimulated Cytokines, Chemokines and T Helper 1/ T Helper 2 Balance in Humans , 2013, PloS one.

[10]  D. Ellard,et al.  Psychological stress and neutrophil activation : the potential for tissue damage and disease. , 2003 .

[11]  Brigitte M. Kudielka,et al.  Delayed response and lack of habituation in plasma interleukin-6 to acute mental stress in men , 2006, Brain, Behavior, and Immunity.

[12]  G. Page,et al.  Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids , 2014, Psychoneuroendocrinology.

[13]  Georg Schett,et al.  Cytokines in the pathogenesis of rheumatoid arthritis , 2007, Nature Reviews Immunology.

[14]  M. Irwin,et al.  Interleukin-6 and Tumor Necrosis Factor-&agr; Production After Acute Psychological Stress, Exercise, and Infused Isoproterenol: Differential Effects and Pathways , 2000, Psychosomatic medicine.

[15]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[16]  Sang-Bum Park,et al.  Relationship between salivary Chromogranin-A and stress induced by simulated monotonous driving , 2009, Medical & Biological Engineering & Computing.

[17]  S. Rubin,et al.  Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study). , 2003, The American journal of cardiology.

[18]  John Spertus,et al.  Use of saliva-based nano-biochip tests for acute myocardial infarction at the point of care: a feasibility study. , 2009, Clinical chemistry.

[19]  Sharon Williams,et al.  What a drop can do: Dried blood spots as a minimally invasive method for integrating biomarkers into population-based research , 2007, Demography.

[20]  J. Aycock,et al.  Use of saliva for assessment of stress and its effect on the immune system prior to gross anatomy practical examinations , 2010, Anatomical sciences education.

[21]  G. Savva,et al.  Inflammation and frailty measures in older people , 2009, Journal of cellular and molecular medicine.

[22]  B. Przewłocka,et al.  Importance of glial activation in neuropathic pain. , 2013, European journal of pharmacology.

[23]  V. Vieira,et al.  Exercise, inflammation, and innate immunity. , 2006, Neurologic clinics.

[24]  E. Gordis,et al.  Salivary alpha-amylase in biobehavioral research: recent developments and applications. , 2007, Annals of the New York Academy of Sciences.

[25]  R. Gräsbeck,et al.  CYTOKINES IN SALIVA. BASAL CONCENTRATIONS AND THE EFFECT OF HIGH AMBIENT HEAT (SAUNA) , 1996 .

[26]  R. Ader,et al.  Brain, behavior, and immunity , 1987, Brain, Behavior, and Immunity.

[27]  B. McEwen Protective and damaging effects of stress mediators. , 1998, The New England journal of medicine.

[28]  L. M. Ibrahim,et al.  Effect of the examination stress on periodontal health status and salivary IL-1? among Iraqi dental students , 2013 .

[29]  B. Giesser Diagnosis of multiple sclerosis. , 2011, Neurologic clinics.

[30]  Jenna L. Riis,et al.  Salivary cytokines in healthy adolescent girls: Intercorrelations, stability, and associations with serum cytokines, age, and pubertal stage. , 2014, Developmental psychobiology.

[31]  A. Steptoe,et al.  The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis , 2007, Brain, Behavior, and Immunity.

[32]  A. Bamberger,et al.  Systemic interleukin‐1 α and interleukin‐2 secretion in response to acute stress and to corticotropin‐releasing hormone in humans * , 1994, European journal of clinical investigation.

[33]  O. Çalıyurt,et al.  Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder , 2003, Psychopharmacology.

[34]  L. Price,et al.  Association between Plasma IL-6 Response to Acute Stress and Early-Life Adversity in Healthy Adults , 2010, Neuropsychopharmacology.

[35]  H. Biesalski,et al.  Concentration of interleukin-1beta and neutrophil elastase activity in gingival crevicular fluid during experimental gingivitis. , 2001, Journal of clinical periodontology.

[36]  Bente Klarlund Pedersen,et al.  Exercise and IL‐6 infusion inhibit endotoxin‐induced TNF‐α production in humans , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  Nicolas Rohleder,et al.  Human salivary alpha-amylase reactivity in a psychosocial stress paradigm. , 2005, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[38]  P. Pasquini,et al.  Effect of Psychological Stress on Salivary Interleukin-1β in Psoriasis , 2007 .

[39]  C. Nemeroff,et al.  Increased Stress-Induced Inflammatory Responses in Male Patients With Major Depression and Increased Early Life Stress , 2006 .

[40]  A. Steptoe,et al.  Socioeconomic status and stress-induced increases in interleukin-6 , 2004, Brain, Behavior, and Immunity.

[41]  S. Maier,et al.  Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia , 2008, Brain, Behavior, and Immunity.

[42]  A. Steptoe,et al.  Psychological stress activates interleukin-1β gene expression in human mononuclear cells , 2005, Brain, Behavior, and Immunity.

[43]  M. Elawad,et al.  Interleukin-10 and Interleukin-10–Receptor Defects in Inflammatory Bowel Disease , 2012, Current Allergy and Asthma Reports.

[44]  J. Morales-Montor,et al.  Interleukin-6: A Cytokine with a Pleiotropic Role in the Neuroimmunoendocrine Network , 2010 .

[45]  P. Nair,et al.  Targeted therapy of bronchitis in obstructive airway diseases. , 2013, Pharmacology & therapeutics.

[46]  K. Morimoto,et al.  Secretory IgA in saliva can be a useful stress marker , 1999, Environmental health and preventive medicine.

[47]  P. Birembaut,et al.  Implication of Interleukin-4 in Wound Healing , 2000, Laboratory Investigation.

[48]  Cindy Munro,et al.  Comparison of Biomarkers in Blood and Saliva in Healthy Adults , 2012, Nursing research and practice.

[49]  J. Goldblatt,et al.  Evolutionary adaptation of inflammatory immune responses in human beings , 2000, The Lancet.

[50]  B. Kudielka,et al.  Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. , 1999, Psychosomatic medicine.

[51]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[52]  A. Heinz,et al.  Effects of acute psychological stress on adhesion molecules, interleukins and sex hormones: implications for coronary heart disease , 2002, Psychopharmacology.

[53]  C. Ring,et al.  Sex differences in the interleukin-6 response to acute psychological stress , 2006, Biological Psychology.

[54]  John T McDevitt,et al.  Current developments in salivary diagnostics. , 2010, Biomarkers in medicine.

[55]  J. Suls,et al.  Associations of Depression With C-Reactive Protein, IL-1, and IL-6: A Meta-Analysis , 2009, Psychosomatic medicine.

[56]  Thomas E. Hughes,et al.  Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[57]  R. Hall,et al.  Assessing salivary C-reactive protein: Longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence , 2012, Brain, Behavior, and Immunity.

[58]  C. Kirschbaum,et al.  Clinical Depression and Regulation of the Inflammatory Response During Acute Stress , 2005, Psychosomatic medicine.

[59]  Jennifer L Martin,et al.  To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers , 2009, Brain, Behavior, and Immunity.

[60]  P. Komi,et al.  Influence of the sample collection method on salivary interleukin–6 levels in resting and post-exercise conditions , 2007, European Journal of Applied Physiology.

[61]  W. Dunlap,et al.  Meta-Analysis of Experiments With Matched Groups or Repeated Measures Designs , 1996 .

[62]  L. Hedges Distribution Theory for Glass's Estimator of Effect size and Related Estimators , 1981 .

[63]  N. Moyna,et al.  Stressor-Induced Alteration of Cytokine Production in Multiple Sclerosis Patients and Controls , 1998, Psychosomatic medicine.

[64]  T. D. Du Clos,et al.  Function of C-reactive protein. , 2000 .

[65]  R. Seymour,et al.  Salivary Proteins and Cytokines in Drug-induced Gingival Overgrowth , 2004, Journal of dental research.

[66]  T. Tözüm,et al.  Relationship between the quantity of gingival crevicular fluid and clinical periodontal status. , 2000, Journal of oral science.

[67]  Richard P. DeShon,et al.  Combining effect size estimates in meta-analysis with repeated measures and independent-groups designs. , 2002, Psychological methods.

[68]  J. Teruya-Feldstein,et al.  Contribution of the CXC chemokines IP‐10 and Mig to the antitumor effects of IL‐12 , 1998, Journal of leukocyte biology.

[69]  G. Miller,et al.  If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. , 2007, Psychological bulletin.

[70]  S. Segerstrom Resources, Stress, and Immunity: An Ecological Perspective on Human Psychoneuroimmunology , 2010, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[71]  T. Hirano,et al.  Excessive production of interleukin 6/B cell stimulatory factor‐2 in rheumatoid arthritis , 1988, European journal of immunology.

[72]  I. Aimone-Gastin,et al.  Effects of psycho–physical stress (competitive rafting) on saliva interleukin‐1 beta , 2001 .

[73]  Shelly L. Gable,et al.  Social-Evaluative Threat and Proinflammatory Cytokine Regulation , 2009, Psychological science.

[74]  M. Irwin,et al.  Inflammatory responses to psychological stress in fatigued breast cancer survivors: Relationship to glucocorticoids , 2007, Brain, Behavior, and Immunity.

[75]  Linda R Watkins,et al.  Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. , 2002, Physiological reviews.

[76]  Alamgir Khan,et al.  Detection and quantitation of forty eight cytokines, chemokines, growth factors and nine acute phase proteins in healthy human plasma, saliva and urine. , 2012, Journal of proteomics.

[77]  Maria Alice d´Ávilla Becker,et al.  Psychological Stress and Its Influence on Salivary Flow Rate, Total Protein Concentration and IgA, IgG and IgM Titers , 2010, Neuroimmunomodulation.

[78]  C. Hunter New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions , 2005, Nature Reviews Immunology.

[79]  J. Kocki,et al.  IL-1α and IL-1β Levels in Blood Serum and Saliva of Menopausal Women , 2013, Endocrine research.

[80]  S. Dickerson,et al.  Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. , 2004, Psychological bulletin.

[81]  J. Bosch The use of saliva markers in psychobiology: mechanisms and methods. , 2014, Monographs in oral science.

[82]  I. Lamster,et al.  Inflammatory biomarkers in saliva: assessing the strength of association of diabetes mellitus and periodontal status with the oral inflammatory burden. , 2012, Journal of clinical periodontology.

[83]  R. Deinzer,et al.  Acute stress effects on local Il-1β responses to pathogens in a human in vivo model , 2004, Brain, Behavior, and Immunity.

[84]  J. Albandar Periodontal diseases in North America. , 2002, Periodontology 2000.

[85]  C. Engeland,et al.  Sex hormones and mucosal wound healing , 2009, Brain, Behavior, and Immunity.

[86]  Andrew H. Miller,et al.  Cytokines sing the blues: inflammation and the pathogenesis of depression. , 2006, Trends in immunology.

[87]  J. Smyth,et al.  Ecological momentary interventions: incorporating mobile technology into psychosocial and health behaviour treatments. , 2010, British journal of health psychology.

[88]  C. Kirschbaum,et al.  Impact of oral contraceptive use on glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress , 2003, Psychoneuroendocrinology.

[89]  I. Lamster,et al.  The diagnostic applications of saliva--a review. , 2002, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[90]  H. DeVon,et al.  The Association of Pain With Protein Inflammatory Biomarkers: A Review of the Literature , 2014, Nursing research.

[91]  D. Verthelyi Sex Hormones and the Immune System , 2003 .

[92]  A. Rainoldi,et al.  Differential responses of serum and salivary interleukin-6 to acute strenuous exercise , 2005, European Journal of Applied Physiology.

[93]  K. Salomon,et al.  Salivary Measures of Stress and Immunity in Police Officers Engaged in Simulated Critical Incident Scenarios , 2010, Journal of occupational and environmental medicine.

[94]  J. Campisi,et al.  Acute psychosocial stress differentially influences salivary endocrine and immune measures in undergraduate students , 2012, Physiology & Behavior.

[95]  S. Segerstrom Personality and the immune system: Models, methods, and mechanisms , 2000, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[96]  A. Minagar,et al.  The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis , 2002, Journal of the Neurological Sciences.

[97]  F. Balkwill TNF-α in promotion and progression of cancer , 2006, Cancer and Metastasis Reviews.

[98]  U. Nater,et al.  Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: Current state of research , 2009, Psychoneuroendocrinology.

[99]  M. Mehl,et al.  Handbook of research methods for studying daily life , 2012 .

[100]  Nicolas Rohleder,et al.  Chronic Interpersonal Stress Predicts Activation of Pro- and Anti-Inflammatory Signaling Pathways 6 Months Later , 2009, Psychosomatic medicine.

[101]  L. Hawkley,et al.  Loneliness , dysphoria , stress and immunity : A role for cytokines , 2007 .

[102]  J. O’Shea,et al.  The biology of IL-12: coordinating innate and adaptive immune responses. , 2003, Cytokine & growth factor reviews.

[103]  G. Beall,et al.  Infection with HIV is associated with elevated IL-6 levels and production. , 1990, Journal of immunology.

[104]  J. Larue,et al.  Lecturing to 200 students and its effects on cytokine concentration and salivary markers of adrenal activation. , 2011, Stress and health : journal of the International Society for the Investigation of Stress.

[105]  T. Yoshikawa,et al.  EFFECTS OF ACUTE PROLONGED STRENUOUS EXERCISE ON THE SALIVARY STRESS MARKERS AND INFLAMMATORY CYTOKINES , 2011 .

[106]  A Steptoe,et al.  Acute mental stress elicits delayed increases in circulating inflammatory cytokine levels. , 2001, Clinical science.

[107]  C. Kirschbaum,et al.  The 'Trier Social Stress Test'--a tool for investigating psychobiological stress responses in a laboratory setting. , 1993, Neuropsychobiology.

[108]  A. Steptoe,et al.  The Effects of Effort-Reward Imbalance on Inflammatory and Cardiovascular Responses to Mental Stress , 2006, Psychosomatic medicine.

[109]  Joanna M. Young,et al.  Inflammatory biomarkers for predicting cardiovascular disease. , 2013, Clinical biochemistry.

[110]  R. Faith,et al.  Stress and Immunity , 1991 .

[111]  Jing Du,et al.  A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. , 2009, The international journal of neuropsychopharmacology.

[112]  L. Marnell,et al.  C-reactive protein: ligands, receptors and role in inflammation. , 2005, Clinical immunology.

[113]  J. Cacioppo,et al.  Mucosal wound healing: the roles of age and sex. , 2006, Archives of surgery.

[114]  S. Boyle,et al.  Increases in stimulated secretion of proinflammatory cytokines by blood monocytes following arousal of negative affect: The role of insulin resistance as moderator , 2006, Brain, Behavior, and Immunity.

[115]  M. Gröschl,et al.  Salivary cytokines in cell proliferation and cancer. , 2011, Clinica chimica acta; international journal of clinical chemistry.

[116]  G. Kamimori,et al.  Psychological stress during exercise: immunoendocrine and oxidative responses , 2010, Experimental biology and medicine.

[117]  M. Irwin,et al.  Sleep depth and fatigue: Role of cellular inflammatory activation , 2011, Brain, Behavior, and Immunity.

[118]  M. Heineman,et al.  Sex hormones and the immune response in humans. , 2005, Human reproduction update.

[119]  E. Bosmans,et al.  The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. , 1998, Cytokine.

[120]  Craig S. Miller,et al.  Lab‐on‐a‐Chip Methods for Point‐of‐Care Measurements of Salivary Biomarkers of Periodontitis , 2007, Annals of the New York Academy of Sciences.

[121]  S. Maier,et al.  Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids , 2007, Brain, Behavior, and Immunity.

[122]  M. Visser,et al.  Endocrine and inflammatory markers as predictors of frailty , 2005, Clinical endocrinology.

[123]  Petros P Sfikakis,et al.  The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. , 2010, Current directions in autoimmunity.

[124]  F. Balkwill TNF-alpha in promotion and progression of cancer. , 2006, Cancer metastasis reviews.

[125]  T. Tabuchi,et al.  Immune function and lifestyle of taxi drivers in Japan. , 1998, Industrial health.

[126]  M. Navazesh,et al.  Methods for Collecting Saliva , 1993, Annals of the New York Academy of Sciences.

[127]  M. Rauh,et al.  Evaluation of saliva collection devices for the analysis of steroids, peptides and therapeutic drugs. , 2008, Journal of pharmaceutical and biomedical analysis.

[128]  A. Danese,et al.  Validation of a high-sensitivity assay for C-reactive protein in human saliva , 2010, Brain, Behavior, and Immunity.

[129]  J. Hural,et al.  Functions of IL-4 and control of its expression. , 1997, Critical reviews in immunology.

[130]  J. Dowd,et al.  Socioeconomic Differentials in Immune Response , 2009, Epidemiology.

[131]  J. Krueger,et al.  Biochemical regulation of sleep and sleep biomarkers. , 2011, Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine.

[132]  R. Jurevic,et al.  Reduced systemic inflammatory mediators after treatment of chronic gingivitis. , 2013, Saudi medical journal.

[133]  A. Steptoe,et al.  Inflammatory cytokines, socioeconomic status, and acute stress responsivity , 2002, Brain, Behavior, and Immunity.

[134]  A. Facciorusso,et al.  Salivary markers of work stress in an emergency team of urban police (1 degree step). , 2006, Giornale italiano di medicina del lavoro ed ergonomia.

[135]  K. Kostner,et al.  One-step homogeneous C-reactive protein assay for saliva. , 2011, Journal of immunological methods.

[136]  C. Dinarello,et al.  Immunological and inflammatory functions of the interleukin-1 family. , 2009, Annual review of immunology.

[137]  D. Opriș,et al.  Detection of Homocysteine and C-Reactive Protein in the Saliva of Healthy Adults: Comparison with Blood Levels , 2010, Biomarker insights.

[138]  F. Dhabhar,et al.  Stress-induced changes in skin barrier function in healthy women. , 2001, The Journal of investigative dermatology.

[139]  C. Heeschen,et al.  Serum Level of the Antiinflammatory Cytokine Interleukin-10 Is an Important Prognostic Determinant in Patients With Acute Coronary Syndromes , 2003, Circulation.

[140]  C. Ring,et al.  Increased C reactive protein in response to acute stress in patients with rheumatoid arthritis , 2005, Annals of the rheumatic diseases.