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Blood, Vol. 109, Issue 9, 3640-3648, May 1, 2007
Mast cell–derived TNF can promote Th17 cell–dependent neutrophil recruitment in ovalbumin-challenged OTII mice
Blood Nakae et al.
109: 3640
Supplemental materials for: Nakae et al, Vol 109, Issue 9, 3640-3648
Files in this Data Supplement:
- Table S1. Effects of deficiencies of cytokines, receptors, or mast cells on numbers of BAL fluid leukocytes 24 hours after OVA challenge in OTII mice (PDF, 446 KB)
- Figure S1. LPS-induced airway neutrophilia can be induced independently of IL-1R1, IL-18, TNF, and mast cells (PDF, 313 KB) -
Wild-type mice (n = 12), IL-18–/– mice (n = 10), IL-1R1–/– mice (n = 12), TNF–/– mice (n = 10), and KitW-sh/W-sh mice (n = 10) received 10 µg of LPS intranasally, and cells in BALF were quantified 24 hours later. Data are the average + SD of results pooled from 2 independent experiments, each of which gave similar results. None of the differences in the values obtained in mice of different genotypes were statistically significant (ie, all comparisons were P > .05).
- Figure S2. Evidence that histamine, PGD2, CXCL10, LTB4, and IL-16 are not essential for Th17 cell–mediated neutrophilic airway inflammation (PDF, 896 KB) -
Mice were treated with or without the indicated specific antagonist before OVA or PBS inhalation. For histamine receptor antagonist treatment, mice were injected with pyrilamine (Sigma; 50 mg/kg; as in Jawdat et al1), cimetidine (Sigma; 50 mg/kg; as in Jawdat et al1) or thioperamide (Sigma; 10 mg/kg, as in Tamaoki et al2) intraperitoneally 30 minutes before OVA or PBS inhalation (once per day for 3 days). For PGD2 receptor antagonist treatment, mice were injected with BW A868C (Cayman Chemical; 1 mg/kg; as in Shiraishi et al3) and BAY-u3405 (Cayman Chemical; 10 mg/kg; as in Shiraishi et al3) intravenously 1 hour before OVA or PBS inhalation (once per day for 3 days). For LTB4 receptor antagonist treatment, mice were given SB-209247 (Glaxo Smith Kline; 25 mg/kg; as in Daines et al4) perorally 1 hour before OVA or PBS inhalation (once per day for 3 day). Mice were treated intraperitoneally with anti-rat CXCL10 (200 µg; as in Morimoto et al5), kindly provided by Dr Shosaku Narumi (University of Tokyo), or control mouse IgG, on day –1, 0, and 2 before the last OVA challenge. Mice then were treated with 50 µg of OVA or PBS intranasally for 3 days (once per day). Cells in BALF were quantified 24 hours after the last inhalation. (A) Vehicle-injected OTII mice (PBS, n = 6; OVA, n = 10), H1 antagonist (pyrilamine)–treated OTII mice (PBS, n = 6; OVA, n = 10), H2 antagonist (cimetidine)–treated OTII mice (PBS, n = 6; OVA, n = 10) and H3 and H4 antagonist (thioperamide)–treated OTII mice (PBS, n = 6; OVA, n = 10). (B) Vehicle-injected OTII mice (PBS, n = 6; OVA, n = 8), DP1 antagonist (BW A868C)–treated OTII mice (PBS, n = 6; OVA, n = 11), and DP2/CRTH2 antagonist (BAY-u3405)–treated OTII mice (PBS, n = 6; OVA, n = 8). (C) Vehicle-injected OTII mice (PBS, n = 6; OVA, n = 12), BLT1 antagonist (SB-209247)–treated OTII mice (PBS, n = 5; OVA, n = 11). (D) IL-16+/+ OTII mice (PBS, n = 8; OVA, n = 10), and IL-16–/– OTII mice (PBS, n = 6; OVA, n = 10). (E) OTII mice treated with control mouse IgG (PBS, n = 5; OVA, n = 8), and OTII mice treated with anti-rat CXCL10 mAb (PBS, n = 5; OVA, n = 8). *P < .01 versus corresponding values for PBS-treated mice (A-E); †P < .05 versus corresponding values for OVA-treated IL-16–/– OTII mice (D). Data are the average + SD of results pooled from 2 or 3 independent experiments, all of which gave similar results.
Rationale for experiments in Figure S2
Mast cells can produce many mediators, including histamine, serotonin (in rodents), arachidonic acid derivatives (e.g., PGD2 and LTB4), and several cytokines, growth factors, and chemokines, all of which can also be produced by other cell types.6,7 Although histamine and PGD2 can each contribute to neutrophil recruitment,8,9 OVA-challenged OTII mice pretreated with the H1, H2, or H3 and H4 receptor antagonists pyrilamine, cimetidine, or thioperamide, respectively, did not exhibit significant reductions in numbers of BALF neutrophils or other leukocytes (Figure S2A). Pretreatment of OTII mice with BW A868C or BAY-u3405, antagonists for PGD2 receptors DP1 or DP2/CRTH2, respectively, also was without significant effects on BALF leukocytes (Figure S2B).
LTB4 can promote neutrophil recruitment,10 and mast cell–derived LTB4 can contribute to the recruitment of CD8+ T cells.11 However, treatment with SB-209247, an antagonist for the LTB4 receptor, BLT1, did not significantly influence numbers of OVA-induced neutrophils in BALF (Figure S2C). IL-16, which is produced by mast cells and other cell types,7,12 can induce recruitment of CD4+ T cells.12 IL-16 deficiency resulted in impaired lymphocyte recruitment, but the more modest reduction in BALF neutrophil numbers in IL-16–/– OTII mice was not significant (Figure S2D).
Th17 cells can express certain Th1 lineage markers such as IL-18R and CXCR3,13-15 suggesting that IL-18 and CXCL10 may contribute to the development of certain biological responses through effects on Th17 cells rather than (or, in addition to) via effects on Th1 cells. IL-18 and CXCL10 mRNA are expressed in mast cells,7 and both IL-1816-18 and CXCL1019 are thought to contribute to the development of Th17 cell– rather than Th1 cell–associated immune responses. However, experiments in OTII mice treated with an anti-CXCL10 neutralizing mAb indicated that CXCL10 did not significantly influence the development of neutrophilic airway inflammation in this model (Figure S2E).
These results strongly suggest that the development of Th17 cell–mediated neutrophilic airway inflammation in this model can occur independently of histamine, PGD2, LTB4, or CXCL10, and with little or no contribution of IL-16.
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