A distinct immune cytokine profile is associated with morning cortisol and repeated stress


  • Rebecca Ryznar, PhD https://orcid.org/0000-0001-9695-712X
  • Anthony LaPorta, MD
  • Spencer Cooper
  • Nicholas Maher
  • Christian Clodfelder, MS, DO
  • Jeffrey Edwards
  • Francina Towne, PhD
  • K. Dean Gubler, DO, MPH




stress, cytokines, mass casualty, simulation training, immune response


Objective: The objective of this study was to investigate possible immune cytokine trends throughout a week-long surgical simulation mass-casualty training session in order to determine the effects of stress inoculation on the immune system.

Methods: Thirty-seven military medical students participated in a hyper-realistic surgical simulation training event conducted at Strategic Operations site in San Diego, California. Salivary samples were collected every morning of the stress training exercise for 4 consecutive days. Cortisol, along with a panel of 42 immune cytokines, was measured using multiplex enzyme-linked immunosorbent assays from Eve Technologies. The determined concentrations were averaged and plotted on a scatter plot, and then points were fit to a second-order polynomial trendline of best fit to measure.

Results: The cytokines epidermal growth factor, growth-related oncogene-α, interleukin (IL)-1α, and platelet-derived growth factor-AA followed a noted pattern of cortisol decrease throughout the week. In addition, cytokines IL-27, granulocyte colony stimulating factor, IL-10, and IL-13 demonstrated a late peak, followed by a return to baseline at the conclusion of training. Finally, the cytokine monocyte chemoattractant protein-1 displayed a decline throughout the week followed by an increase on the last day of stress training.

Conclusions: Altogether, these results help to identify important biomarkers that may help to improve long-term stress adaptation and prevent post-traumatic stress disorder following exposure to repeated stress.

Author Biographies

Rebecca Ryznar, PhD

Associate Professor, Molecular Biology, Department of Biomedical Sciences, Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Anthony LaPorta, MD

Director, Military Medicine Program; Professor, Clinical Surgery, Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Spencer Cooper

Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Nicholas Maher

Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Christian Clodfelder, MS, DO

Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Jeffrey Edwards

Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

Francina Towne, PhD

Program Director, Master of Science in Biomedical Sciences Program; Associate Professor of Immunology, Department of Biomedical Sciences, Rocky Vista University College of Osteopathic Medicine, Parker, Colorado

K. Dean Gubler, DO, MPH

Professor, Surgery and Military Medicine; Director, Military Medicine Program, Rocky Vista University College of Osteopathic Medicine, Parker, Colorado


Morey JN, Boggero IA, Scott AB, et al.: Current directions in stress and human immune function. Curr Opin Psychol. 2015; 5: 13-17. DOI: 10.1016/j.copsyc.2015.03.007.

Salleh MR: Life event, stress and illness. Malays J Med Sci. 2008; 15(4): 9-18.

Bellavance MA, Rivest S: The HPA—Immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front Immunol. 2014; 5: 136. DOI: 10.3389/fimmu.2014.00136.

Menard C, Pfau M, Hodes G, et al.: Immune and neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsychopharmacology. 2017; 42: 62-80. DOI: 10.1038/npp.2016.90.

Boggero I, Hostinar C, Haak E, et al.: Psychosocial functioning and the cortisol awakening response: Meta-analysis, P-curve analysis, and evaluation of the evidential value in existing studies. Biol Psychol. 2017; 129: 207-230. DOI: 10.1016/j.biopsycho.2017.08.058.

Powell DJ, Schlotz W: Daily life stress and the cortisol awakening response: Testing the anticipation hypothesis. PLoS One. 2012; 7(12): E52067.

McEwen BS, Nasca C, Gray JD: Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016; 41(1): 3-23. DOI: 10.1038/npp.2015.171.

Hoang TN, LaPorta AJ, Malone JD, et al.: Hyper-realistic and immersive surgical simulation training environment will improve team performance, trauma surg. Trauma Surg Acute Care Open. 2020; 5: E000393. DOI: 10.1136/tsaco-2019-000393.

LaPorta AJ, McKee J, Hoang T, et al.: Stress inoculation: Preparing outside the box in surgical resuscitation and education. Curr Trauma Rep. 2017. DOI: 10.1007/s40719-017-0090-2.

Zapata I, Farrell J, Morrell S, et al.: Emotional intelligence, cortisol and α-amylase response to highly stressful hyper-realistic surgical simulation of a mass casualty event scenario. Compr Psychoneuroendocrinol. 2021; 5: 100031. DOI: 10.1016/J.CPNEC.2021.100031.

Ryznar R, Wong C, Onat E, et al.: Principal component analysis of salivary cytokines and hormones in the acute stress response. Front Psychiatry. 2022; 13: 957545. DOI: 10.3389/fpsyt.2022.957545.

Lai JCL, Leung MOY, Lee DYH, et al.: Biomarking trait resilience with salivary cortisol in Chinese undergraduates. Front Psychol. 2020; 11: 536510. DOI: 10.3389/fpsyg.2020.536510.

Yeager MP, Pioli PA, Guyre PM: Cortisol exerts bi-phasic regulation of inflammation in humans. Dose Response. 2011; 9(3): 1-347. DOI: 10.2203/dose-response.10-013.

Berlanga-Acosta J, Gavilondo-Cowley J, Lopez-Saura P, et al.: Epidermal growth factor in clinical practice—A review of its biological actions, clinical indications and safety implications. Int Wound J. 2009; 6(5): 331-346. DOI: 10.1111/j.1742-481X.2009.00622.x.

Herbst RS: Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004; 59(2): 21-26.

Asberg M, Nygren A, Leopardi R, et al.: Novel biochemical markers of psychosocial stress in women. PLoS One. 2009; 4(1): E3590. DOI: 10.1371/journal.pone.0003590.

Zhang Q, Liu G, Wu Y, et al.: BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/akt pathway. Molecules. 2011; 16(12): 10146-10156. DOI: 10.3390/molecules161210146.

Cohen I, Rider P, Vornov E, et al.: IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. 2015; 5: 14756. DOI: 10.1038/srep14756.

Pearson-Leary J, Eacret D, Bhatnagar S: Interleukin-1α in the ventral hippocampus increases stress vulnerability and inflammation-related processes. Stress. 2020; 23(3): 308-317. DOI: 10.1080/10253890.2019.1673360.

Lee DY, Kim E, Choi MH: Technical and clinical aspects of cortisol as a biochemical marker of chronic stress. BMB Rep. 2015; 48(4): 209-216. DOI: 10.5483/bmbrep.2015.48.4.275.

Long KLP, Chao LL, Kazama Y, et al.: Regional gray matter oligodendrocyte-and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans. Transl Psychiatry. 2021; 11: 631. DOI: 10.1038/s41398-021-01745-5.

Tang L, Cai N, Zhou Y, et al.: Acute stress induces an inflammation dominated by innate immunity represented by neutrophils in mice. Front Immunol. 2022; 13: 1014296. DOI: 10.3389/fimmu.2022.1014296.

Abdalla AE, Li Q, Xie L, et al.: Biology of IL-27 and its role in the host immunity against mycobacterium tuberculosis. Int J Biol Sci. 2015; 11(2): 168-175. DOI: 10.7150/ijbs.10464.

Rudak PT, Choi J, Parkins KM, et al.: Chronic stress physically spares but functionally impairs innate-like invariant T cells. Cell Rep. 2021; 35(2): 108979. DOI: 10.1016/j.celrep.2021.108979.

Ambree O, Ruland C, Zwanzger P, et al.: Social defeat modulates T helper cell percentages in stress susceptible and resilient mice. Int J Mol Sci. 2019; 20(14): 3512. DOI: 10.3390/ijms20143512.

Li H, Linjuan L, Wang Y: G-CSF improves CUMS-induced depressive behaviors through downregulating ras/ERK/MAPK signaling pathway. Biochem Biophys Res Commun. 2016; 479(4): 827-832. DOI: 10.1016/j.bbrc.2016.09.123.

Szabo YZ, Newton TL, Miller JJ, et al.: Acute stress induces increases in salivary IL-10 levels. Stress. 2016; 19(5): 499-505.

Kim C, Schinkel C, Fuchs D, et al.: Interleukin-13 effectively down-regulates the monocyte inflammatory potential during traumatic stress. Arch Surg. 1995; 130(12): 1330-1336.

Tian R, Hou G, Li D, et al.: A possible change process of inflammatory cytokines in the prolonged chronic stress and its ultimate implications for health. Sci World J. 2014; 2014: 1-8. DOI: 10.1155/2014/780616.

Priyadarshini S, Aich P: Effects of psychological stress on innate immunity and metabolism in humans: A systematic analysis. PLoS One. 2012; 7(9): e43232. DOI: 10.1371/journal.pone.0043232.

Madrigal JL, Garcia-Bueno B, Hinojosa AE, et al.: Regulation of MCP-1 production in brain by stress and noradrenaline-modulating drugs. J Neurochem. 2010; 113(2): 543-551. DOI: 10.1111/j.1471-4159.2010.06623.x.

West E, Singer-Chang G, Ryznar R, et al.: The effect of hyper-realistic trauma training on emotional intelligence in second year military medical students. J Surg Educ. 2020; 77(6): 1422-1428.

Dhabhar FS, Malarkey WB, Neri E, et al.: Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones–Curt Richter award winner. Psychoneuroendocrinology. 2012; 37(9): 1345-1368.



How to Cite

Ryznar, R., A. LaPorta, S. Cooper, N. Maher, C. Clodfelder, J. Edwards, F. Towne, and K. D. Gubler. “A Distinct Immune Cytokine Profile Is Associated With Morning Cortisol and Repeated Stress”. American Journal of Disaster Medicine, vol. 19, no. 1, Feb. 2024, pp. 33-43, doi:10.5055/ajdm.0468.