Z. Xing et al., IL-6 IS AN ANTIINFLAMMATORY CYTOKINE REQUIRED FOR CONTROLLING LOCAL OR SYSTEMIC ACUTE INFLAMMATORY RESPONSES, The Journal of clinical investigation, 101(2), 1998, pp. 311-320
IL-6 is induced often together with the proinflammatory cytokines TNF
alpha and IL-1 in many alarm conditions, and circulating IL-6 plays an
important role in the induction of acute phase reactions. However, wh
ether this endogenous IL-6 plays any additional pro-or antiinflammator
y 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 p
roinflammatory cytokines TNF alpha and MIP-2 and a neutrophilic respon
se in the lung of IL-6+/+ mice. However, the levels of TNF alpha and M
IP-2 and neutrophilia were significantly higher in the lung of IL-6-/-
mice. The rate of neutrophil apoptosis in these mice was similar to t
hat in IL-6+/+ mice. A low constitutive level of antiinflammatory cyto
kine IL-10 was not enhanced by endotoxin and remained similar in the l
ung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal de
livery of endotoxin resulted in much more pronounced circulating level
s of TNF alpha, MIP-2, GM-CSF, and IFN gamma in IL-6-/- mice than in I
L-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice ab
olished these differences. In contrast, circulating IL-10 levels were
induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, ou
r studies reveal that endogenous IL-6 plays a crucial antiinflammatory
role in both local and systemic acute inflammatory responses by contr
olling the level of proinflammatory, but not antiinflammatory, cytokin
es, and that these antiinflammatory activities by IL-6 cannot be compe
nsated for by IL-10 or other IL-6 family members.