Haptoglobin dampens endotoxin‐induced inflammatory effects both in vitro and in vivo

Abstract

Summary We report that haptoglobin, an acute‐phase protein produced by liver cells in response to interleukin‐6 (IL‐6), can modulate the inflammatory response induced by endotoxins. We provide evidence that haptoglobin has the ability to selectively antagonize lipopolysaccharide (LPS) effects in vitro by suppressing monocyte production of tumour necrosis factor‐α, IL‐10 and IL‐12, while it fails to inhibit the production of IL‐6, IL‐8 and IL‐1 receptor antagonist. In two animal models of LPS‐induced bronchopulmonary hyperreactivity and endotoxic shock, haptoglobin knockout mice were more sensitive to LPS effects compared to their wild‐type counterparts. The present data suggest that haptoglobin regulates monocyte activation following LPS stimulation. The increase in haptoglobin levels during an acute‐phase reaction may generate a feedback effect which dampens the severity of cytokine release and protects against endotoxin‐induced effects.

Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice

“…Although there may be several substances involved in this phenomenon, one candidate might be haptoglobin, which was recently demonstrated to suppress TNF-␣, IL-12, and IL-10 from human peripheral blood mononuclear cells in vitro. 29 We also obtained a similar finding that RAW cells produced a lesser amount of TNF-␣ upon LPS stimulation in the presence of haptoglobin ( Supplementary Fig. 2).…”

Acute phase gene expression in rainbow trout (Oncorhynchus mykiss) after exposure to a confinement stressor: A comparison of pooled and individual data

“…Haptoglobin also has an inhibitory effect on granulocyte chemotaxis, phagocytosis and bactericidal activity (Rossbacher et al, 1999) and may inhibit mast cell proliferation (El-Ghmati et al, 2002), prevent spontaneous maturation of epidermal Langerhans cells (Xie et al, 2000) or suppress T-cell proliferation (Arredouani et al, 2003). Haptoglobin produced by liver cells in mice in response to interleukin-6 (IL-6) has been demonstrates to modulate the inflammatory response induced by endotoxins (Arredouani et al, 2005). The multiple and varied immunoregulatory effects of haptoglobin may provide an explanation for the up-regulation of this acute phase gene in during instances of both invasive and non-invasive stress.…”

Identification of a specific haptoglobin C‐terminal fragment in arthritic synovial fluid and its effect on interleukin‐6 expression

“…[9][10][11] In the present study, C-term Hp induced IL-6 expression in monocytic cells, whereas native Hp did not show the activity of IL-6 induction at an equimolar concentration. This suggests that structural modifications or differences must be considered in terms of Hp action.…”

“…9 The inhibitory function of Hp in endotoxin-induced inflammation was also reported both in vitro and in vivo. 10 Based on these findings, Hp has been considered an antiinflammatory regulator and a tissue protector. However, Shen et al 11 showed recently that Hp stimulates the production of interleukin-6 (IL-6) and tumour necrosis factor-a via a MyD88-dependent pathway in CD11c + dendritic cells and activates innate immunity in a mouse model of skin transplantation, which resulted in acute transplant rejection.…”