Psychological Stress and Cytokines: Where Mind and Body Meet

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Psychological Stress and CytokinesWhere Mind
and Body Meet

• Barry Thompson, MD
• Seattle University
• October, 2007

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This Talk Will Cover

• I. Basic definitions
• II. How the body responds to stress
• III. What pro-inflammatory cytokines are
• IV. How they act
• V. Their contribution to physical and
  psychological disorders within the mind-body
  dynamic

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Stress Defined

• The state which results from some physical or
  psychological threat to ones homeostasis that in
  turn activates certain systems within the body,
  resulting in physiological change and a response
  to the threat.

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Medical Definitions

• Autonomic nervous system (sympathetic and
  parasympathetic divisions) blood pressure, heart
  rate, sweating, digestion, pupil size, etc.
• Endothelial cells line blood vessels
• Atherosclerosis narrowing of blood vessels by
  plaques in blood-vessel lining (hardening of
  the arteries)
• Glial cells (mainly astrocytes) cells that
  support neurons in the brain

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Medical Definitions

• Blood-brain barrier specialized barrier between
  bloodstream and the brain
• Peripheral nerves nerves to parts of the body,
  extending outward from the brain and spinal cord
• Paraganglia local groupings of nerve cells
  outside of the CNS
• HPA axis regulates stress response

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Hypothalamic-Pituitary-Adrenal Axis (HPA-Axis)

• Mechanism by which the body responds to a
  stressful stimulus (such as fight-or-flight)
• Hypothalamus stimulates pituitary to stimulate
  the adrenal glands
• Adrenal glands release adrenaline, cortisol
  (stress hormone)
• Results in increased blood pressure, heart rate,
  alertness, readiness to respond to threat
• Also results in proinflammatory cytokine
  elevation

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HPA Axis
Maier, Watkins (1998)
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What Are Cytokines?

• A diverse group of medium-sized proteins
• Act in very small concentrations (ppm, ppb)
• Regulate the activities of a wide variety of
  cells and tissues
• Are active in both normal and pathological
  conditions

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Cytokines

• Generally act over short distances and time spans
• Made widely in the body-brain, liver, immune
  system, fat cells, endothelial cells (cells that
  line blood vessels)
• Are able to cross the blood-brain barrier

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What Do They Do?

• Cell differentiation (how specialized cells
  develop)
• Regulate cell growth and repair
• Crucial role in inflammation
• Act as messengers between the brain and immune
  system
• Different cells may respond differently to the
  same cytokine
• Act by binding to specific membrane receptors

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Pro-Inflammatory Cytokine Images
Tumor Necrosis Factor (TNF)
Interleukin Family
Source http//www.copewithcytokines.de/
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Specific Pro-inflammatory Cytokines

• Interleukin-1
• Interleukin-2
• Interleukin-6
• Tumor necrosis factor alpha
• Interferon gamma
• IL-6, TNF-alpha increase with normal aging
  (higher
• levels in men)

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Cytokines Are Part of the Neuro-Immune System

• An interdependent network involving communication
  between the nervous system, immune system, and
  endocrine system (specialized glands that secrete
  hormones)
• Forms the basis of what has come to be known as
  the mind-body connection

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The Neuro-Immune System

• A highly complex sensory organ
• Senses changes in environment, and responds
• HPA axis, cytokines able to powerfully influence
  bodily systems
• Directly links the CNS and the rest of the body

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The Neuro-Immune System

• Information exchanged back and forth between
  immune system and brain
• Communication via cytokines as well as by direct
  cell contact
• Emotional factors play a crucial role in cytokine
  release
• Via cytokines, emotions can have major impact
  upon long-term health

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Therefore, the nervous system is no longer
considered to act in an isolated manner via
cytokines, the brain is able to directly
influence both inflammation and cell regulation
in a wide variety of processes.
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Cytokine Effects

• Outside the brain
• Atherosclerosis-increases risk of heart attack,
  high blood pressure
• Thrombosis (clotting within blood vessels)
• Increased risk of diabetes
• Lead to development of certain cancers (leukemia,
  Non-Hodgkins Lymphoma, Multiple Myeloma)
• Implicated in auto-immune diseases (arthritis,
  lupus)
• Osteoporosis

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• Inside the brain
• Released by glial support cells (mainly
  astrocytes) in response to psychological stress
• Initiate inflammatory response
• Help regulate HPA-axis
• May worsen certain auto-immune brain disorders,
  such as multiple sclerosis
• High concentrations of IL-2 receptors in
  hippocampus (important in memory)
• Act on multiple neurotransmitter systems
  (dopamine, serotonin, acetylcholine,
  noradrenaline) that affect mood and cognition
• Promote neuronal degeneration and death

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Cytokines and Physical Stress

• Immune system ? brain pathway (direct)

• cytokines released by WBCs in response to
  infection, injury
• cytokines can enter the brain by crossing the
  blood-brain barrier

Maier, Watkins (1998)
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Cytokines and Physical Stress

• Immune system ? brain pathway (indirect)

• communicate with the brain by way of the
  peripheral nerves

Maier, Watkins (1998)
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Either directly or indirectly, once the cytokine
message gets to the brain

• Bind to other support cells (astrocytes)
  neurons
• Support cells then make their own cytokines
• Result ? typical sick feeling and behavior
• ? appetite
• confused thinking
• ? anxiety
• sleep disturbances
• ? pleasure (anhedonia)
• HPA axis ? more cytokines released outside brain

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Cytokines and Psychological Stress

• Cytokines have been shown to rise inside and
  outside
• the brain in relation to psychological stress
  such as
• performance of a stressful task
• exposure to a psychological stressor

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Cytokines and Psychological Stress

• Involves the sympathetic nervous system

• Cytokine levels in rats rise even when adrenals
  have been removed

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Cytokines and Psychological Stress

• Steptoe et al (2001)
• incongruous color naming
• mirror tracing with high expectations

• Cytokines measured at 45 minutes 2 hours
• blood levels of IL-6 ? 56

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Cytokines and Chronic Psychological Stress

• Robles et al (2005)
• Adults caring for spouse with Alzheimers showed
  4x annual increase in IL-6 production
• This did not change even several years after
  caregiving ceased (followed for 6 years)
• Chronic stress can result in long-term increases
  in
• pro-inflammatory cytokines, above and beyond
• normal aging, even after stressor removed

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Cytokines and the Brain in Chronic Stress

• ? Neuron formation
• ? Neuron loss, including hippocampus (memory)
• Regular exercise may mitigate effects of chronic
  stress by way of ? brain cytokines
• Implicated in Alzheimers Disease, Parkinsons
  Disease, pseudo-dementia, depression

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Cytokines and Depression

• Depression is common in many medical conditions
  implies more than just primary psychological
  cause
• Major depression common in interferon therapy in
  cancer and hepatitis C (36)
• Antidepressant drugs possess some
  anti-inflammatory propertiesmay partly account
  for their effects (by blocking cytokine-induced
  inflammation)
• Cytokines released during a viral illness may
  cause relapse

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Cytokines and Depression

• Initially increase serotonin activity
• Simultaneously inhibit serotonin synthesis
• Net effect ?? serotonin
• Also acts on serotonin receptors to ? activity
• Therefore, chronic stress reduces serotonin
  and contributes to depression

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Brain Serotonin Pathways

• Widely distributed throughout the brain
• Particularly numerous in cortex, limbic system
  (emotions and memory), basal ganglia, and
  hypothalamus
• May explain why depression affects not only mood,
  but sleep, libido, appetite, memory

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Cytokines and Schizophrenia

• IL-2 can cause schizophrenia-like symptoms
  (directly proportional to dose)
• Up to 65 of patients receiving high-dose IL-2
  developed delusions and severe cognitive
  impairment
• ? IL-6 levels in blood of people with
  schizophrenia
• Neuroleptics inhibit production and/or release of
  cytokines

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Cytokines and Aging

• Serum IL-6 and TNF-alpha increase with normal
  aging (higher levels in men)
• Higher levels correlate with impaired cognitive
  ability and may predict future cognitive decline
• Increased risk of vascular dementia
• ? IL-6 levels associated with higher
  morbidity/mortality even after controlling for
  demographic factors and health behaviors

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Summary Risks

• Atherosclerosis, diabetes
• High blood pressure, stroke, heart attack
• Certain cancers
• Vascular dementia, AD, PD
• Depression
• Premature aging, general physical decline
• Arthritis, osteoporosis

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What Can Be Done?

• Mitigate stress level (relaxation exercises,
  meditate, alter lifestyle, or anything else that
  reduces personal stress)
• Regular exercise (lowers cytokine levels)
• Diet higher omega-3/omega-6 PUFA levels reduce
  pro-inflammatory cytokine response to stress
• Think Happy Thoughts!