Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters

Behavioral researchers have increasingly become interested in the idea that chronic, low-grade inflammation is a pathway through which social and behavioral variables exert long-term effects on health. Much research in the area employs putative inflammatory biomarkers to infer an underlying state of inflammation. Interleukin 6 (IL-6) and C-reactive protein (CRP, whose production is stimulated by IL-6) are arguably the two most commonly assayed biomarkers. Yet, in contrast with near-universal assumptions in the field, discoveries in immunology over the past two decades show that neither IL-6 nor CRP are unambiguous inflammatory markers. IL-6 operates through two distinct signaling pathways, only one of which is specifically upregulated during inflammation; both pathways have a complex range of effects and influence multiple physiological processes even in absence of inflammation. Similarly, CRP has two isoforms, one of which is produced locally in inflamed or damaged tissues. The other isoform is routinely produced in absence of inflammation and may have net anti-inflammatory effects. We propose a functional framework to account for the multiple actions of IL-6 and CRP. Specifically, we argue that both molecules participate in somatic maintenance efforts; hence elevated levels indicate that an organism is investing in protection, preservation, and/or repair of somatic tissue. Depending on the state of the organism, maintenance may be channeled into resistance against pathogens (including inflammation), pathogen tolerance and harm reduction, or tissue repair. The findings and framework we present have a range of potential implications for the interpretation of empirical findings in this area—a point we illustrate with alternative interpretations of research on socioeconomic status, stress, and depression.