Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters
Introduction
An important goal of the behavioral sciences is to understand the physiological mechanisms through which environmental factors influence behavior and health. Increasingly, researchers have focused on the immune system and particularly on inflammation, a nonspecific response against actual or potential infections. Inflammatory pathways are intertwined with those that regulate stress and metabolism; for this reason, inflammation can be a physiological nexus though which a wide range of psychosocial, socioeconomic, and nutritional factors exert their effects. These factors do not produce the high-intensity inflammatory responses that occur in acute infections but rather have been linked to chronic states of “low-grade” activation of the same biochemical pathways (see Fagundes and Way, 2014, Kuhlman et al., 2017, Miller et al., 2011, Minihane et al., 2015).
Inflammation is an intricate process involving dozens of molecules. The majority of studies in this area have employed two functionally linked biomarkers—the cytokine interleukin 6 (IL-6) and the acute phase protein C-reactive protein (CRP), whose production in the liver is stimulated by IL-6. These molecules are easy to detect in serum and are secreted in large amounts during infections. In the behavioral literature, IL-6 and CRP are unanimously regarded as inflammatory biomarkers, and both are commonly used to assess the presence and severity of low-grade inflammation (e.g., Baumeister et al., 2016, Fagundes and Way, 2014, Miller et al., 2011). Recent examples with a focus on psychosocial factors include studies of the effects of financial stress on inflammation (Sturgeon et al., 2016), developmental trajectories of stress exposure and inflammation in adolescence (Ehrlich et al., 2016), and inflammation as a mediator between stressful life events across the life course and telomere length in middle age (Osler et al., 2016). Large-scale epidemiological studies and meta-analyses yield evidence for robust associations of IL-6 and CRP with mortality outcomes due to a variety of causes, including cancer, cardiovascular disease, and metabolic syndrome (e.g., Schnabel et al., 2013, Singh-Manoux et al., 2017, Li et al., 2017), with some associations likely being stronger in men (e.g., cancer; Li et al., 2017).
Despite scholars within the behavioral sciences treating and utilizing IL-6 and CRP as markers of inflammation, each with pro-inflammatory effects, recent research in immunology questions this assumption. As we discuss in detail below, IL-6 acts through two distinct signaling pathways; depending on which one operates, it may be part of an inflammatory response or have effects in absence of inflammation. Indeed, some effects of IL-6 are best described as anti- rather than pro-inflammatory. Likewise, CRP is involved in inflammation but also in many other processes related to tissue maintenance, and plays both pro- and anti-inflammatory roles within the immune system. Its varied roles partly stem from the fact that CRP exists in two isoforms with markedly different functions, only one of which (the one less strongly tied to inflammation) is routinely measured in the behavioral and biomedical literature. These important findings are widely recognized in the field of immunology but virtually never appreciated in the behavioral sciences.
Our first goal in this paper is to summarize relevant findings from the immunological literature concerning the multiple functions of IL-6 and CRP. These findings challenge the idea that IL-6 and CRP are simply “inflammatory biomarkers,” and suggest that moderately elevated levels of these molecules may reflect physiological states other than low-grade chronic inflammation. To gain more insight into the possible alternative interpretations of elevated IL-6 and CRP, we then place the action of these molecules in a broader functional perspective by (a) framing immunity and tissue repair as two overlapping aspects of somatic maintenance, the organism’s investment in the integrity and functionality of the body (Del Giudice et al., 2015, Roff, 2002); and (b) considering the key distinction between resistance and tolerance in the immune response to pathogens (Ayres and Schneider, 2012, Medzhitov et al., 2012). Drawing on this framework, we discuss the implications for research examining associations between environmental factors and elevated IL-6 and CRP. We illustrate our points by considering possible alternative interpretations of empirical findings on the immunological correlates of socioeconomic status, stress, and depression.
Section snippets
Inflammation
Inflammation is a nonspecific immune response to actual or potential infections (see Ashley et al., 2012, Lochmiller and Deerenberg, 2000, Parkin and Cohen, 2001). In an acute inflammatory reaction, molecular patterns that indicate microbial invasion, tissue damage, or exposure to foreign particles are detected and trigger an inflammatory response. The response is coordinated by a number of cytokines, the signaling proteins of the immune system. Among the most important cytokines involved in
Rethinking the role of IL-6
When inflammation is triggered, IL-6 is released into circulation (by neutrophils and macrophages, as well as resident cells at the site of infection or damage), partly induced by IL-1β and TNF-α. One major effect of IL-6 is to stimulate the production of CRP and other acute phase proteins (e.g., serum amyloid P component, serum amyloid A, fibrinogen, ferritin) in the liver and their release into the bloodstream. IL-6 similarly stimulates production of neutrophils in bone marrow, which are then
Rethinking the role of CRP
CRP is an acute phase protein produced in the liver and secreted into the bloodstream during an inflammatory episode, largely in response to IL-6 signaling (and, to a lesser extent, IL-1β and other pro-inflammatory cytokines). As IL-6 rises during acute inflammation, the concentration of CRP in plasma increases dramatically too, from less than 1 μg/mL to up to 1000 μg/mL in severe systemic infections or extensive burns. CRP levels begin to rise 4–6 h after the start of infection and peak about
A Functional perspective
In the preceding sections, we provided an up-to-date summary of the many physiological actions of IL-6 and CRP, both during acute inflammation and in absence of an inflammatory reaction. The findings we reviewed are inconsistent with simple pro-inflammatory accounts in the prevailing behavioral literature. At the same time, these findings currently lack an alternative theoretical account. In an effort to address this lacuna, we now draw on concepts from life history theory and theoretical
Summary
To summarize, both IL-6 and CRP participate in processes of somatic maintenance—specifically, immunity and tissue repair. Furthermore, IL-6 promotes maintenance through its metabolic effects (e.g., stimulation of lipolysis). Similar to a related hormone, leptin, IL-6 levels reflect storage of energy in the form of deposited fat. The production of IL-6 in adipocytes, then, may be a mechanism whereby organisms increase allocation to ongoing somatic maintenance, contingent upon availability of
Implications for research
The expanded view of IL-6 and CRP we presented in this paper has important implications for understanding the causal processes that give rise to empirical findings, particularly in areas where these biomarkers have been interpreted by default as indicators of ongoing inflammation. In many such areas, existing findings may hide a considerable amount of heterogeneity. Individuals with moderately elevated IL-6 and/or CRP do not necessarily suffer from chronic low-grade inflammation; in an unknown
Summary and conclusion
In recent years, researchers have sought to integrate the behavioral, neurobiological, and immunological perspectives in a coherent, powerful way that speaks to how social contexts, lifestyles, and behavior exert long-term effects on physical and psychological health. These efforts have deservedly generated much excitement. A burgeoning empirical literature links current and developmental conditions (e.g., experiences of stress, obesity, hormonal exposures, infectious disease) with measured
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