The induction of interleukin (IL)-32 in bone marrow (BM) inflammation is crucial in graft versus host disease (GvHD) that is a common side effect of allogeneic BM transplantation. Clinical trials on α-1 antitrypsin (AAT) in patients with GvHD are based on the preliminary human and mouse studies on AAT reducing the severity of GvHD. Proteinase 3 (PR3) is an IL-32-binding protein that was isolated from human urine. IL-32 primarily induces inflammatory cytokines in myeloid cells, probably due to PR3 expression on the membrane of the myeloid lineage cells. The inhibitory activity of AAT on serine proteinases may explain the anti-inflammatory effect of AAT on GvHD. However, the anti-inflammatory activity of AAT on BM cells remains unclear. Mouse BM cells were treated with IL-32γ and different inflammatory stimuli to investigate the anti-inflammatory activity of AAT. Recombinant AAT-Fc fusion protein inhibited IL-32γ-induced IL-6 expression in BM cells, but failed to suppress that induced by other stimuli. In addition, the binding of IL-32γ to PR3 was abrogated by AAT-Fc. The data suggest that the specific anti-inflammatory effect of AAT in mouse BM cells is due to the blocking of IL-32 binding to membrane PR3.

中文翻译：

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IL-32 诱导的炎症细胞因子在小鼠骨髓细胞中被 α1-抗胰蛋白酶选择性抑制

骨髓 (BM) 炎症中白介素 (IL)-32 的诱导在移植物抗宿主病 (GvHD) 中至关重要，这是同种异体 BM 移植的常见副作用。α-1 抗胰蛋白酶 (AAT) 在 GvHD 患者中的临床试验是基于人类和小鼠对 AAT 降低 GvHD 严重程度的初步研究。蛋白酶 3 (PR3) 是一种从人尿中分离的 IL-32 结合蛋白。IL-32 主要诱导骨髓细胞中的炎性细胞因子，这可能是由于骨髓谱系细胞膜上的 PR3 表达。AAT 对丝氨酸蛋白酶的抑制活性可以解释 AAT 对 GvHD 的抗炎作用。然而，AAT 对 BM 细胞的抗炎活性仍不清楚。用 IL-32γ 和不同的炎症刺激物处理小鼠 BM 细胞以研究 AAT 的抗炎活性。重组 AAT-Fc 融合蛋白抑制 IL-32γ 诱导的 BM 细胞 IL-6 表达，但未能抑制其他刺激诱导的表达。此外，AAT-Fc 取消了 IL-32γ 与 PR3 的结合。数据表明 AAT 在小鼠 BM 细胞中的特异性抗炎作用是由于阻断了 IL-32 与膜 PR3 的结合。