Inflammatory cytokines in experimental and human stroke

Abstract

Inflammation is a hallmark of stroke pathology. The cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, modulate tissue injury in experimental stroke and are therefore potential targets in future stroke therapy. The effect of these cytokines on infarct evolution depends on their availability in the ischemic penumbra in the early phase after stroke onset, corresponding to the therapeutic window (<4.5 hours), which is similar in human and experimental stroke. This review summarizes a large body of literature on the spatiotemporal and cellular production of TNF, IL-1, and IL-6, focusing on the early phase in experimental and human stroke. We also review studies of cytokines in blood and cerebrospinal fluid in stroke. Tumor necrosis factor and IL-1 are upregulated early in peri-infarct microglia. Newer literature suggests that IL-6 is produced by microglia, in addition to neurons. Tumor necrosis factor- and IL-1-producing macrophages infiltrate the infarct and peri-infarct with a delay. This information is discussed in the context of suggestions that neuronal sensitivity to ischemia may be modulated by cytokines. The fact that TNF and IL-1, and suppossedly also IL-6, are produced by microglia within the therapeutic window place these cells centrally in potential future stroke therapy.

Figure 1

Dynamics of the recruitment of the penumbra into the infarct in experimental stroke. (A) Schematic presentation of the penumbra and infarct early within the acute phase, when the penumbra may still be recruited into the infarct, if the ischemic process is not counteracted by, e.g., reperfusion or neuroprotective intervention. The penumbra is given as the mismatch between the area of reduced protein synthesis and the area of reduced ATP levels exactly 1 hour after proximal middle cerebral artery occlusion (MCAO) in a C57Bl/6 mouse, and is drawn from coronal brain sections shown in Figure 1 in Hata et al (2000b). (B) Graphic presentation illustrating the difference in the recruitment of the penumbra into the infarct after transient MCAO (tMCAO) and permanent MCAO (pMCAO) in the mouse. The dotted line represents the total infarct volume. The vertical distance between the dotted line, and the blue and red line, respectively, represents the size of the penumbra after pMCAO and tMCAO. At 24 hours, the penumbra has been completely recruited into the infarct after pMCAO, but not after tMCAO, in which case the penumbra initially expands due to the reperfusion, whereafter it gradually regresses. As above, the penumbra is defined as the percent mismatch between the area of reduced protein synthesis and the area of reduced ATP levels, starting 1 hour after MCAO, at which time the penumbra is similar in tMCAO and pMCAO. The graph is reconstructed from data in Hata et al (2000a, 2000b).

Figure 2

Effect of therapeutic or genetic manipulation of tumor necrosis factor (TNF), interleukin (IL)-1β, or IL-6 bioavailability on infarct size in experimental stroke. Graphic presentation of studies showing a neuroprotective (black) or neurotoxic (white) effect of therapeutic intervention or genetic manipulation of TNF, IL-1β, or IL-6 or their receptors in rodents after transient MCAO (tMCAO) or permanent MCAO (pMCAO). Data are presented as the percent difference in total infarct volume between the experimental and the control group, giving rise to an increase (bars directed to the right) or a decrease (bars directed to the left) in lesion size. Unless stated data were obtained from studies using 24-hour post-surgery survival. Further details on doses and experimental settings are given in Tables 1A, 1B, 1C. bp, binding protein; i.c.v., intracerebroventricular; i.p., intraperitoneal; i.v., intravenous; KO, knock out; mAb, monoclonal antibody; pAb, polyclonal antibody. ^*P<0.05, ^**P<0.01, ^***P<0.001.

Figure 3

Temporal cytokine messenger RNA (mRNA) profile in experimental stroke. Graphic presentations of the temporal mRNA profiles of tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6 mRNA in the acute phase (<4 to 6 hours) and up till 24 hours after permanent MCAO (pMCAO) and transient MCAO (tMCAO) in mice (solid lines) and rats (dotted lines). Data are presented as relative increases in mRNA levels on an abitrary y axis and the peak time of expression after surgery on the x axis. Data for TNF were obtained from: solid blue and red (Hill et al, 1999); solid green (Lambertsen et al, 2009); and dotted blue (Liu et al, 1994) and red (Berti et al, 2002). Data for IL-1β were obtained from: solid blue and red (Hill et al, 1999); solid green (Clausen et al, 2005); dotted blue (Wang et al, 1994); dotted red (Berti et al, 2002); and dotted green (Wang et al, 2000). Data for IL-6 were from: solid blue and red (Hill et al, 1999), dotted blue (Wang et al, 1995); and dotted red (Berti et al, 2002).

Figure 4

Temporal profile of tumor necrosis factor (TNF) and interleukin (IL)-1β messenger RNA (mRNA) upregulation after permanent MCAO (pMCAO) in mice. Graphic presentation of the temporal mRNA profile of TNF and IL-1β in the same ischemic hemispheres from mice subjected to pMCAO. Data are presented as relative increases in cytokine mRNA levels compared with unmanipulated controls, and have been obtained from Clausen et al (2005) and Lambertsen et al (2009). Note both increase in cytokine levels in the early phase (<4 to 6 hours) after MCAO, and the different profiles of TNF mRNA and IL-1β mRNA expression through 12 and 24 hours after MCAO. Although, only the TNF mRNA level, but not the IL-1β mRNA level, was significantly elevated compared with unmanipulated control and sham-operated mice in the early phase, cells expressing low levels of IL-1β mRNA were observed to be present the ischemic territory from 2 hours after MCAO (Clausen et al, 2005).