IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.

TLDR

IL‑6 is produced alongside TNFα and IL‑1 during inflammatory stimuli and drives acute‑phase responses, yet its additional pro‑ or anti‑inflammatory functions remain uncertain. This study aimed to determine IL‑6’s role in acute inflammation. The authors compared IL‑6+/+ and IL‑6‑/‑ mice in endotoxic lung and endotoxemia models to assess inflammatory outcomes. IL‑6‑/‑ mice exhibited markedly higher lung and systemic pro‑inflammatory cytokines and neutrophilia, which recombinant IL‑6 reversed, demonstrating that endogenous IL‑6 exerts a critical anti‑inflammatory effect by limiting pro‑inflammatory cytokine production that cannot be compensated by IL‑10 or other IL‑6 family members.

Abstract

IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.