Department of Medicine, University of Louisville, Louisville, KY, United States.
Department of Medicine, Robley Rex VA Medical Center, Louisville, KY, United States.
Front Immunol. 2023 Dec 14;14:1202267. doi: 10.3389/fimmu.2023.1202267. eCollection 2023.
Changes in the expression of cyto- and chemokines due to alcohol-associated liver disease (ALD) have been reported to be both protective and pathogenic. This study examined plasma levels of two key cytokines, Il-17 and Il-22, which construct the proinflammatory vs. anti-inflammatory axes across the spectrum of alcohol use disorder (AUD) and ALD including alcohol-associated hepatitis (AH) to determine the underlying status of the inflammation.
Forty-two males and females aged 25-63 yrs. were grouped as healthy controls (HV[n=8]), AUD with no liver injury (AUDNLI [n=8]), AUD with liver injury (AUDLI [n=8]), non-severe alcohol-associated hepatitis (NSAH [n=9]), and severe alcohol-associated hepatitis (SAH [n=9]). Demographic, drinking, and clinical data were collected. Blood samples were collected at baseline (BL, all subjects) and during week 4 (W4, only patients) for IL-17 and IL-22; and statistically analyzed.
IL-17 was highly elevated in the SAH group both at BL and post-SOC. LTDH and BL IL-22 in non-severe AH patients were associated significantly. LTDH significantly predicted W4 IL-22 levels, positively (increasing) in NSAH and inversely (lowering) in SAH patients. BL and W4 IL-22 levels were significantly higher (4-fold, p≤0.001) in all AH patients compared to all AUD patients (AUROC=0.988, p≤0.001). IL-22 showed significant affinity with AST, AST: ALT ratio, total bilirubin, INR, and PT both at BL and W4. IL-22 was inversely associated with IL-1β; and positively with TNF-α and IL-8 both at BL, and W4. BL IL-17 showed a positive correlation with MELD (p=0.017) in all AH patients. In SAH, > 2-fold W4 IL-17 level compared to BL showed significant within subjects' effects, p=0.006. In AUD patients without AH, the drop in IL-17 at W4 vs. BL showed a significant within subjects' effect, p=0.031.
Drinking chronicity predicted opposite effects in IL-22 levels in NSAH (antiinflammatory) and SAH (pro-inflammatory) patients at post-SOC. BL IL-22 levels differentiated AH patients robustly from the AUD patients (with or without liver injury); and showed corresponding increases stepwise with the stages of ALD. IL-22 was closely associated with progression and injury markers of the liver; and response to the cytokines of pro-inflammatory nature. Pro-inflammatory indicator of IL-17 cell axis, IL-17 showed a strong positive association with MELD, a severity indicator of AH.
由于酒精相关性肝病（ALD），细胞因子和趋化因子的表达发生变化，被认为具有保护作用和致病性。本研究检测了两种关键细胞因子（IL-17 和 IL-22）的血浆水平，它们在酒精使用障碍（AUD）和 ALD 谱中构建了促炎与抗炎轴，包括酒精相关性肝炎（AH），以确定炎症的潜在状态。
42 名年龄在 25-63 岁的男性和女性被分为健康对照组（HV[n=8]）、无肝损伤的 AUD（AUDNLI[n=8]）、有肝损伤的 AUD（AUDLI[n=8]）、非严重酒精相关性肝炎（NSAH[n=9]）和严重酒精相关性肝炎（SAH[n=9]）。收集人口统计学、饮酒和临床数据。所有受试者均在基线（BL）采集血液样本，仅患者在第 4 周（W4）采集血液样本，用于检测 IL-17 和 IL-22；并进行统计学分析。
SAH 组在 BL 和 SOC 后 IL-17 均显著升高。非严重 AH 患者的 LTDH 和 BL IL-22 显著相关。LTDH 显著预测 NSAH 患者的 W4 IL-22 水平，呈正相关（增加），而在 SAH 患者中呈负相关（降低）。所有 AH 患者的 BL 和 W4 IL-22 水平均显著高于所有 AUD 患者（AUROC=0.988，p≤0.001）（4 倍，p≤0.001）。BL 和 W4 的 IL-22 水平与 AST、AST：ALT 比值、总胆红素、INR 和 PT 均显著相关。IL-22 与 BL 和 W4 的 IL-1β呈负相关；与 TNF-α和 IL-8 呈正相关。BL 的 IL-17 与所有 AH 患者的 MELD 呈正相关（p=0.017）。在 SAH 中，与 BL 相比，W4 时 >2 倍的 IL-17 水平显示出显著的受试者内效应，p=0.006。在没有 AH 的 AUD 患者中，与 BL 相比，W4 时 IL-17 的下降显示出显著的受试者内效应，p=0.031。
在 SOC 后，IL-22 水平在 NSAH（抗炎）和 SAH（促炎）患者中呈现出相反的慢性饮酒作用。BL 的 IL-22 水平可将 AH 患者与 AUD 患者（有或无肝损伤）区分开来；并且随着 ALD 阶段的进展，IL-22 水平呈逐步增加。IL-22 与肝脏损伤和进展标志物密切相关；并与促炎细胞因子的反应相关。IL-17 细胞轴的促炎标志物 IL-17 与 MELD（AH 严重程度的标志物）呈强正相关。
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