Essential role of neutrophil mobilization in concanavalin A-induced hepatitis is based on classic IL-6 signaling but not on IL-6 trans-signaling

Abstract

Neutrophil depleted mice are protected from concanavalin A-mediated hepatitis, showing that neutrophils are critical for cellular liver damage. Interleukin-6 has pro- and anti-inflammatory properties and mediates neutrophil recruitment in diseases such as rheumatoid arthritis. In classic signaling, interleukin-6 binds to the membrane-bound interleukin-6-receptor and initiates signaling via gp130. In interleukin-6 trans-signaling, the agonistic soluble interleukin-6-receptor can form a soluble interleukin-6/interleukin-6-receptor complex and stimulate cells which only express gp130 but no interleukin-6-receptor. Interleukin-6 trans-signaling was shown to be important for liver regeneration and development of liver adenomas. Here, we show that blocking classic interleukin-6 signaling but not interleukin-6 trans-signaling reduced concanavalin A-induced liver damage in mice, with reduced liver STAT3 phosphorylation and liver neutrophil accumulation. However, the level of neutrophil-attracting chemokine KC is only reduced by inhibition of interleukin-6 trans-signaling. Analysis of circulating neutrophils after concanavalin A challenge revealed that classic interleukin-6 signaling is required for the mobilization of blood neutrophils. Reduced neutrophil infiltration was accompanied by increased levels of hepatoprotective monocyte chemoattractant protein-1 and reduced level of hepatodestructive interleukin-4. Abrogated classic interleukin-6 signaling in concanavalin A-mediated hepatitis exhibited liver-protective effects indicating that interleukin-6 classic but not interleukin-6 trans-signaling is responsible for liver damage. Classic interleukin-6 signaling is required to mount an efficient neutrophilia during concanavalin A-induced immune response, which might have clinical implications in the regard that blocking global interleukin-6 signaling pathways is a treatment option in different chronic inflammatory diseases.

Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis

“…In the present work we clearly demonstrated that the lack of IL-6 resulted in weaker inflammation (IL-6, IFNγ) and blunted acute phase response (SAP, HPTGN) in agreement with the known hepatotoxic effect of IL-6 in liver injury [23] and IL-6 involvement in leukocyte recruitment in liver disease [24]. Interestingly, other authors have suggested a hepatoprotective effect of IL-6.…”

Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update

“…sIL-6R binds to IL-6 with comparable affinity as the mbIL-6R (21); consequently, the complex of IL-6/sIL-6R can activate gp130, a membrane protein is ubiquitously expressed (22–25). Activation of gp130 via the IL-6/sIL-6R complex is termed IL-6 trans-signaling pathway, whereas activation of gp130 via the mbIL-6R is named IL-6 classic signaling pathway (23, 26–28). IL-6 trans-signaling represents an alternative to classic IL-6 signaling and permits IL-6 to modulate a broad spectrum of target cells [Figure S2 in Supplementary Material, quoted from Ref.…”

Superpulsed laser therapy on healing process after tooth extraction in patients waiting for liver transplantation

“…Thus the involvement of IL-6 on facilitating wound healing must be also considered as a possibility, based on their stimulation of keratinocyte proliferation. It has also been evidenced that IL-6 favours the liver regeneration [23].…”

“…IL-6 has pro-and anti-inflammatory functions and controls regenerative processes including wound healing and liver regeneration [23].…”