The Spit Report -- Salimetrics

Volume 4, Number 4, October 2011 - Salimetrics


The study of inflammation and its effects on human health has been a major topic of interest in recent decades. Numerous studies have observed that a low-level state of systemic inflammation is a common feature found in metabolic diseases such as obesity, insulin resistance, and diabetes, as well as in a range of other conditions including cardiovascular disease, cancer, and autoimmune diseases. (See review by Hotamisligil 2006) This common inflammatory state involves a shift in the balance of pro- and anti-inflammatory polypeptide mediators known as cytokines, which in turn leads to changes in levels other inflammatory biomarkers, including acute phase proteins such as C-reactive protein. (Ganter, et al. 1989)

In addition to these changes in physical health, studies have also found that systemic inflammation can be involved in changes in brain health. Psychoneuroimmunologists now recognize that the brain and the immune system communicate through a group of common signaling molecules, which include cytokines, neuropeptides, and neurotransmitters. (See retrospective reviews: Blalock 2005, Dantzer & Kelley 2007, Dinarello 2007, and Irwin 2008.) The details of how peripheral cytokines communicate with the brain are not yet entirely clear, but a number of likely pathways have been proposed and are under investigation. Once these cytokine signals reach the brain they are believed to influence the levels of mood-relevant neurotransmitters such as serotonin, norepinephrine, and dopamine, which then affect behavior.

Stress, Inflammation, and Health Effects
Figure 1. Stress, Inflammation, and Health Effects (Adapted in part from Miller, et al. 2009)

One major development in this field has been the realization that the connection between the brain and peripheral inflammation works in a bi-directional fashion. Studies have shown that psychosocial stress can activate the systemic inflammatory cytokine response, and it is believed that this response in turn can lead back to changes in brain function and the development of mental diseases such as major depressive disorder. (See reviews: Debnath, et al. 2011; Leonard 2010; Miller, et al. 2009; and Dantzer, et al. 2008)

Questions concerning the relationship between inflammation and the brain remain to be resolved, however. For example, it is uncertain whether systemic inflammation alone accelerates the progression of psychiatric disorders, or whether the peripheral and central inflammatory systems operate in parallel to increase the risk of the disorders. (Debnath, et al. 2011) Additionally, it has been noted that inflammatory markers are not always elevated in clinically depressed patients. (Dantzer, et al. 2008)

The review by Miller et al. summarizes a pathway by which stress, operating through the sympathetic nervous system (SNS), can lead to elevated peripheral cytokine levels. In this scheme, catecholamines released from the SNS act through alpha- and beta-adrenergic receptors on macrophages and other immune cells to activate signaling pathways, including the inflammatory transcriptional factor NF-κB.  NF-κB signaling then induces the immune cells to release pro-inflammatory cytokines in response to the stress.

Since uncontrolled inflammation has negative effects on health, the brain recognizes the elevated systemic cytokine levels and induces the HPA axis to increase cortisol secretion, which dampens the inflammatory response by inhibiting the NF-κB signaling. Inhibitory parasympathetic nervous system (PNS) activity and possibly feedback mechanisms within the SNS are also thought to be involved in the control of the inflammatory response. (Rohleder 2011; Sternberg 2006)

Salivary Cytokines

Research involving salivary cytokines has grown over the last decade, and these studies have most often focused on periodontal disease or other oral diseases such as Sjögren’s syndrome, oral lichen planus, and fungal infections. The study of the inflammatory cytokine response to stress has largely utilized in vitro or serum measurements of these markers, but studies are now beginning to explore relationships between stress, brain function, and salivary cytokines, as well.


Stress, Inflammation, and Health Effects
Figure 2. Growth in studies discussing salivary IL-6, 2000-2011.

A major issue that has prevented salivary cytokines from becoming more widely adopted in general psychobiological research is that studies have generally found that salivary levels of these markers correlate only modestly to serum values. (Minetto, et al. 2005; Sjögren, et al. 2006; Fernandez-Botran, et al. 2011) The apparent lack of correlation is not surprising, due to the multiple paths of entry into saliva that exist for these biomarkers. In addition to being produced locally in the saliva glands, cytokines are produced in a variety of mucosal tissues and immune cells in the mouth, and they may also enter through micro-injuries or by transudation from blood. (Schapher, et al. 2011; Dongari-Bagtzoglou, et al. 2005) The permeability of membranes in oral tissues changes in response to infection and inflammation, hormone levels, and – as is suggested in one of the studies featured in this issue – perhaps even by autonomic nervous control; both long- and short-term changes in the contributions from blood are therefore likely to occur.

Because the salivary glands and other tissues in the mouth are also affected by the same outflow of autonomic nervous signals that govern systemic cytokine increases, it seems likely that salivary cytokines will be found to have uses in psychobiological studies. The next generation of studies will need to explore these markers carefully in order to understand the nature of their relationships to stress and various disease states.

To illustrate the potential value of salivary cytokines for biomedical research, in this issue of The Spit Report we feature several research papers that have examined relationships between psychosocial stress, salivary cytokines, and brain function related to mental health. In addition, a small number of exploratory studies have also begun to appear in recent years that have reported relationships between salivary cytokines and diseases in tissues remote from the oral cavity; examples of these are included below under Additional Reading.

Refrences >



Collecting and Handling Saliva Samples for Cytokine Analysis

Studies that include measurements of cytokines in saliva are increasing in number, but information on the best ways to collect and handle the saliva samples is still limited for these analytes.

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