IL-1β/IL-6/CRP and IL-18/ferritin: Distinct Inflammatory Programs in Infections

Abstract

The host inflammatory response against infections is characterized by the release of pro-inflammatory cytokines and acute-phase proteins, driving both innate and adaptive arms of the immune response. Distinct patterns of circulating cytokines and acute-phase responses have proven indispensable for guiding the diagnosis and management of infectious diseases. This review discusses the profiles of acute-phase proteins and circulating cytokines encountered in viral and bacterial infections. We also propose a model in which the inflammatory response to viral (IL-18/ferritin) and bacterial (IL-6/CRP) infections presents with specific plasma patterns of immune biomarkers.

Fig 1. The acute inflammatory response mediated by the release of pro-inflammatory cytokines.

Following PAMP or DAMP recognition, PRRs trigger proinflammatory and antimicrobial responses by inducing the release of a broad range of cytokines. The archetypical pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 are rapidly released upon PRR activation, and they all act as endogenous pyrogens by increasing the hypothalamic thermoregulatory set-point [82]. In addition, TNF-α and IL-1β orchestrate the release of chemokines and expression of leukocyte adhesion molecules on vascular endothelium, promoting the rapid and efficient recruitment of leukocytes towards inflammatory foci [–85]. TNF-α is also responsible for multiple hallmark signs of inflammation by inducing local vasodilation (rubor, calor) and vascular leakage (causing swelling) [86, 87]. Furthermore, IL-1β evokes inflammatory hyperalgesia and is well known for its induction of IL-6 [88, 89]. IL-6, in turn, is a major inducer of acute-phase protein production by hepatocytes [90]. PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; PRR, pattern recognition receptor.

Fig 2. Bacterial- and viral-induced inflammation are characterized by differential plasma levels of CRP and ferritin.

(A) Mean or median concentrations of circulating CRP and ferritin in various viral and bacterial infections illustrate that viral infections are generally characterized by high plasma ferritin with concomitant low circulating CRP [, , , , , –94], while bacterial infections are commonly characterized by high plasma CRP levels [–100]. (B) Proposed model in which the induction of IL-1β/IL-6 in response to bacterial infections contributes to elevated plasma levels of CRP, while viral infections are characterized by an IL-18 response, culminating in hyperferritinemia. Importantly, IL-1/IL-6/CRP and IL-18/ferritin do not fully reflect the bacterial-viral infection dichotomy, as various bacterial infections are known to elevate plasma IL-18 levels while some viral infections are known to raise plasma IL-1β levels [72, 73]. The direct correlation between circulating concentrations of IL-18 and ferritin has not yet been investigated and should be assessed in future studies. HCV: hepatitis C virus infection; EBV: Epstein-Barr virus infection; HIV: human immunodeficiency virus infection.