Elevated Tumor Necrosis Factor-a-induced Protein 8-like 2 mRNA from Peripheral Blood Mononuclear Cells in Patients with Acute Ischemic Stroke

Abstract

Background: Tumor necrosis factor-a-induced protein 8-like 2 (TIPE2) is a novel regulator of immunity and protects against experimental stroke. However, the expression and function of TIPE2 in patients with acute ischemic stroke has not been well demonstrated. Methods: A total of 182 consecutive patients with acute ischemic stroke and 40 healthy controls were included during November 2015 to June 2016. The mRNA levels of TIPE2, interleukin(IL)-1β, IL-10, IL-6, nuclear factor(NF)-κβ, activator protein(AP)-1, interferon(IFN)-γ and tumor necrosis factor(TNF)-α from peripheral blood mononuclear cells were determined using real time quantitative reverse transcriptase polymerase chain reaction. The severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. Results: The median mRNA levels of TIPE2, TNF-α, AP-1, IFN-γ and NF-κβ in patients with acute ischemic stroke were significantly higher than healthy controls (all P<0.001, respectively). Of note, TIPE2 mRNA showed an increasing trend on a time-dependent manner after the onset of stroke. Furthermore, TIPE2 mRNA was negatively associated with lesion volumes (r=-0.23, P<0.01), NIHSS(r=-0.15, P<0.05), TNF-α(r=-0.33,P<0.001), AP-1(r=-0.28,P<0.001), IFN-γ (r=-0.16, P<0.05) and NF-κβ (r=-0.13, P<0.05), but positively associated with IL-6(r=0.14, P<0.05) and IL-10(r=-0.31, P<0.001). Hierarchy cluster analysis showed that TIPE2 mRNA has nearest membership with TNF-α, followed by IL-6, NF-κβ, AP-1, IL-10, IL-1β and IFN-γ. In addition, TIPE2 mRNA in survivals (n=149) was significantly higher than nonsurvivals (n=33) (P<0.001), and showed a great odd ratio (0.52, 95% confidence interval: 0.349-0.760, P<0.001) on 3-month mortality. Conclusions: TIPE2 mRNA contributed to the immune response of stroke and might be a potential biomarker for the mortality of acute ischemic stroke.

Keywords: National Institutes of Health Stroke Scale; acute ischemic stroke; mortality; tumor necrosis factor-a; tumor necrosis factor-a-induced protein 8-like 2.

Figure 1

Flowchart for the inclusion of study patients with acute ischemic stroke and healthy controls

Figure 2

Comparsion of TIPE2 mRNA and its associated cytokines in patients with acute ischemic stroke and healthy controls.The gene expressions of TIPE2, TNF-α, AP-1, IFN-γ and NF-κβ in patients with acute ischemic stroke were significantly higher that than in healthy controls (A, C). (B) showed an increasing trend of TIPE2 mRNA level on the time-dependent manner. However, we did not found significant differences of IL-1β, IL-10, IL-6, NF-κβ, AP-1, IFN-γ and TNF-α mRNA levels in AIS patients with different time stage (D).

Figure 3

Associations of TIPE2 mRNA level with clinical parameters in patients with acute ischemic stroke.There was significantly negative correlations with TIPE2 mRNA and lesion volumes, LDH and NIHSS (B, D). However, we did not find any significant associations of TIPE2 mRNA with HsCRP, TG, TC or GFR (Figure A, B and D). TIPE2 mRNA level was significantly negatively associated with TNF-α, AP-1, IFN-γ and NF-κβ, but significantly positively associated with IL-6 and IL-10(A). Furthermore, hierarchy cluster analysis showed that TIPE2 mRNA has nearest membership with TNF-α, followed by IL-6, NF-κβ, AP-1, IL-10, IL-1β and IFN-γ(C).

Figure 4

Comparison of TIPE2 mRNA and its associated cytokines in survivals and nonsurvivals. The median of TIPE2 mRNA in survivals was significantly higher than that in nonsurvivals (A), as well as the same trend for IL-10(B). However, the medians of TNF-α, AP-1, IFN-γ and NF-κβ mRNA levels in survivals were significantly lower than that in nonsurvivals (A). Furthermore, we did not find any significant differences of IL-1β and IL-6 mRNA levels between survivals and nonsurvivals (B).

Figure 5

Odd raitos of TIPE2 and its associated cytokines on the mortality after 3 months.