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Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury. Hemorrhage- and endotoxin-induced lung TNF-α mRNA and protein production, neutrophil accumulation, and protein permeability were dependent on a functional TLR-4. Hemorrhage-induced nuclear factor (NF)-κB activation was independent of functional TLR-4, whereas endotoxin-induced activation of NF-κB requires a functional TLR-4 for full response. Therefore, we conclude that 1) hemorrhage-induced acute lung injury is TLR-4 dependent and 2) hemorrhage has a different and distinct TLR-4-dependent intracellular activation mechanism compared with endotoxemia.

Interleukin (IL)-11 is a growth factor for megakaryocytes, osteoclasts, and intestinal mucosa. IL-11 is also an anti-inflammatory agent, mediating many of its effects by inhibition of the transcriptional activator nuclear factor (NF)-kappa B. The purposes of this study were to examine the effects of IL-11 on human vascular smooth muscle cell (VSMC) proliferation and NF-kappa B activity. VSMC were cultured from human transplant donor aortas, stimulated with basic fibroblastic growth factor (bFGF), and treated with IL-11. VSMC stimulated with bFGF demonstrated an increase in cell number by direct cell counting and mitochondrial activity. IL-11 caused a concentration-dependent decrease in bFGF-induced VSMC proliferation. Furthermore, IL-11 attenuated bFGF-induced increases in cytoplasmic and intranuclear unbound NF-kappa B p65. Similarly, IL-11 attenuated VSMC expression of two NF-kappa B-dependent cytokines, IL-8 and IL-6. Stimulated VSMC did not secrete IL-11, suggesting that endogenous IL-11 did not account for our observations. In conclusion, IL-11 inhibits human VSMC proliferation in vitro and is associated with suppression of NF-kappa B.