Table 3. Time profile and cellular synthesis of TNF, IL-1β, and IL-6 in human stroke.

Stroke severity and sample size	Time point(s) after stroke	Cytokine analysis	Time profile	Cellular synthesis and/or correlation between cytokine levels and stroke severity/outcome	Reference(s)
Postmortem studies in brain tissue
Severe	1–82 days	TNFa	TNF+ cells observed in all ischemic brains. Maximal numbers observed from 3 days	Primarily microglia-macrophages, but also neurons, astrocytes, and endothelial cells	Dziewulska and Mossakowski (2003)
Severe, 16 patients	15 hours–18 days	TNFa	TNF+ cells from 0 to 6 days to 18 days, peak dependent on cell type	TNF+ neurons, peak days 2–3, gone from day 6, TNF+ invading blood cells from day 3, TNF+ astrocytes from 0 to 6 days to 14 days	Sairanen et al (2001)
Severe, 13 patients, including 2 cases of hemorrhage	4 hours–15 months	TNFa	TNF+ cells from 30 hours, gone at 15 months	Predominantly microglia-macrophages, less in astrocytes and neurons	Tomimoto et al (1996)
CSF studies
30 Patients; small infarcts (n=17), large infarcts (n=13), 18 controls	CSF taken at 0–3, 7–9, 21–26 days and 3 months after stroke	TNF, IL-1β, and IL-6b	TNF only increased in patients with white matter damage 3 months after stroke. Elevated IL-1β in severe cases. Peak days 2–3. Increased IL-6, peak days 2–3	Correlation of IL-6, but not TNF and IL-1β, with poor	Tarkowski et al (1995, 1997)
23 Patients	CSF taken within 24 hours	TNFb	Elevated TNF within 24 hours	Correlation of TNF with lesion size and poor outcome	Zaremba and Losy (2001)
231 Patients, no information on severity	CSF taken within 24 hours from 81 patients only	TNF and IL-6b	Elevated TNF and IL-6 in patients that deteriorated	Correlation of IL-6, but not TNF, with early worsening	Vila et al (2000)
95 Patients, severe (n=44), mild–moderate (n=51), 25 controls	CSF taken within 6 hours	TNF, IL-1, and IL-6b	Elevated IL-1, IL-6, and TNF. IL-6 higher in severe stroke compared with mild and moderate	Correlation of IL-6 with lesion size and poor outcome at 1 month	Beridze et al (2011)
Peripheral blood studies
19 Patients within 4 hours	Blood taken at >1, 3, and 10 days	TNF, IL-1β, IL-6, serumb	IL-6 went up rapidly, peaked at 10 hours till 3 days, baseline at 10 days. No changes for IL-1β and TNF	Correlation of IL-6 with lesion size and poor outcome	Fassbender et al (1994)
45 Patients within 72 hours, 40 controls	Blood taken in 1 day (n=35), 48 hours (n=7), −72 hours (n=3)	TNF, IL-1β, IL-6 in serumc	Elevated IL-6, but not IL-1β and TNF, compared with controls	No correlation of IL-6 with lesion size	Ormstad et al (2011)
66 Patients within 20 hours, 32 controls	Blood taken at admission (6 to 29 hours after stroke)	TNF, IL-1β, IL-6 in serumb	Elevated TNF, IL-1β, and IL-6, compared with controls	Inverse correlation of IL-6 with lesion size and poor outcome	Sotgiu et al (2006)
41 Patients within 24 hours, 40 controls	Blood taken at admission, 2, 4, 7, and 10 days	TNF in serumb	TNF was increased compared with controls at 4, 7, and 10 days, peak level day 7	No correlation of TNF with lesion size and poor outcome	Intiso et al (2003)
231 Patients within 24 hours	Blood taken at admission	TNF and IL-6 in plasmab	Elevated TNF and IL-6 in patients that deteriorated	Correlation of IL-6, but not TNF, with early worsening	Vila et al (2000; see also above)
23 Patients within 24 hours	Blood taken at admission	TNF in serumb	Elevated TNF at 24 hours	Correlation of TNF with lesion size and poor outcome	Zaremba and Losy (2001)
11 Patients, 9 controls	Blood taken at 4, 8, 12, 24, 48, and 72 hours, and 7 and 12 days, and 3 and 12 months	IL-6 in serumd	Elevated IL-6 in the first few hours, peak IL-6 between 3 and 7 days, and correlated with infections	Correlation of early IL-6 with lesion size and poor outcome	Waje-Andreassen et al (2005)
42 Patients within 12 hours, 39 controls	Blood taken at admission, 1, 3, 7, and 14 days	IL-6 in serumb	No elevation of IL-6 up to 3 days after stroke, but elevated levels thereafter with peak at 3 days	Correlation of peak IL-6 with poor outcome. Higher IL-6 in patients with territorial compared with lacunar infarcts	Perini et al (2001)
37 Patients within 12 hours	Blood taken at admission, 1, 5 to 7 days after stroke	IL-6 in plasmab	No information provided	Correlation of peak IL-6 with lesion size and poor outcome	Smith et al (2004)
30 Patients within 3 days	Blood taken at 0–3, 7–9, 21–26 days, and 3 months	IL-1βb, IL-6d in serum	Slight elevation of IL-6 but not IL-1β at day 1 and thereafter. Less IL-6 in serum compared with CSF	No correlation of IL-6 with lesion size	Tarkowski et al (1995; see also above)
18 Patients within 24 hours, 25 controls	Blood taken at admission and 24 hours after tPA therapy	TNF, IL-1β, IL-6 in plasmab	Elevated IL-1β and IL-6 compared with controls and before tPA therapy	Correlation of TNF, IL-1β, and IL-6 with poor outcome	Mazzotta et al (2004)
16 Patients within 6 hours, MRI controlled study	Blood taken at admission, and at 12 and 24 hours	TNF, IL-6 in serumb	No elevation of TNF or IL-6	Correlation of IL-6 and TNF with PWI values of lesion size	Montaner et al (2003)
113 Patients, 43 controls	Blood taken at admission	TNF, IL-6 in plasmab	Significant elevation of IL-6 and TNF	Correlation of IL-6 and TNF with early deterioration and poor outcome	Castellanos et al (2002)

CSF, cerebrospinal fluid; IL, interleukin;MRI, magnetic resonance imaging; PWI, perfusion-weighted image; TNF, tumor necrosis factor.

Assay type:

^aImmuno;

^bELISA;

^cBio-Plex human cytokine array;

^dBio- and immuno assays.