Transforming growth factor-β₁ enhances polymorphonuclear leucocyte accumulation in dermal inflammation and transendothelial migration by a priming action

Acute inflammatory reactions are usually characterized by polymorphonuclear leucocyte (PMNL) migration into inflamed tissues. Transforming growth factors-β₁ (TGF-β₁) may be involved in inflammatory reactions but its actions are controversial and require further in vivo studies. We employed a rabbit dermal inflammation model to investigate the effect of TGF-β₁ on PMNL migration induced by cytokines and chemotactic factors, using ⁵¹Cr-labelled leucocytes to quantify PMNL accumulation in dermal lesions. Injection of TGF-β₁, over a wide dose range, alone did not elicit PMNL accumulation (0.14 x 10⁶ PMNL/site). This contrasted with responses to interleukin-1 alpha (IL-1α) (11.8 x 10⁶ PMNL/site), tumour necrosis factor-alpha (TNF-α) (4.5), lipopolysaccharide (LPS) (14.9), FNLP (10.1), or IL-8 (6.6). However, when sites were pretreated for 3 hr with TGF-β₁ (1-10 ng) and subsequently re-injected with the inflammatory stimuli, TGF-β₁ primed the tissue for an enhanced recruitment of PMNL in response to the endothelium-activating inflammatory agents, IL-1α, TNF-α and LPS, but not to IL-8 or FNLP, which are directly PMNL chemotactic. For example, with IL-1α, PMNL accumulation was 205% greater than the additive sum of each response alone (P<0.05). This was confirmed histologically. TGF-β₁ pretreatment enhanced PMNL accumulation over a wide dose range of IL-1α and LPS. TGF-β₁ did not alter the kinetics of IL-1α or LPS-induced PMNL accumulation, but increased the peak rate of accumulation in lesions. Using an in vitro PMNL transendothelial migration system, TGF-β₁ (10 ng/ml) was found to prime the endothelium for responsiveness to a submaximal dose of IL-1α (0.005 ng/ml) or a threshold dose of LPS (0.01 ng/ml), resulting in enhanced PMNL transendothelial migration. Thus, TGF-β₁ may have a role in priming the microvasculature for enhanced PMNL emigration, especially in response to endothelium-activating agents.