Pharmacokinetic Study of rhIL-18BP and Its Effect on Radiation-Induced Cytokine Changes in Mouse Serum and Intestine
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethics Statement
2.2. Mice and Animal Care
2.3. PK Study
2.4. Cytokine Study
2.4.1. Irradiation and rhIL-18BP Treatment
2.4.2. Tissue Collection and Cytokine Multi-Plex Assay
2.5. Statistical Analysis
3. Results
3.1. Pharmacokinetic Analysis of rhIL-18BP in CD2F1 Mice
3.2. Principal Component Analysis of Mouse Serum Cytokines after Irradiation and IL-18BP Treatment
3.3. Significantly Correlated Serum Cytokines
3.4. Individual Mouse Serum Cytokine Changes after 9.0 Gy TBI
3.5. Serum Cytokines That Were Significantly Changed by rhIL-18BP Treatment after 9.0 Gy TBI
3.6. Principal Component Analysis of Mouse Intestinal Cytokines after Irradiation and rhIL-18BP Treatment
3.7. Significantly Correlated Mouse Intestinal Cytokines
3.8. Individual Mouse Intestinal Cytokine Changes after 9.0 Gy TBI
3.9. Intestinal Cytokines Significantly Changed by rhIL-18BP Treatment after 9.0 Gy TBI
3.10. Significantly Correlated Intestinal and Serum Cytokines
4. Discussion
4.1. Pharmacokinetics of hIL-18BP in Human and Mice
4.2. Radiation-Induced Cytokine Storms
4.3. The Effect of rhIL-18BP on the Radiation-Induced Cytokine Changes
4.4. Correlated Cytokines between the Serum and Intestine
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cytokines | 0 Gy Concentration | 9 Gy d3 veh Concentration | p Value d3 veh vs. 0 Gy | 9 Gy d7 veh Concentration | p Value 9 Gy d7 veh vs. 0 Gy | |
---|---|---|---|---|---|---|
1 | MCP-1 | 13.31 ± 1.97 | 495.87 ± 194.8 | p < 0.05 | 138.79 ± 32.75 | n.s |
2 | MDC | 325.67 ± 42.59 | 513.38 ± 72.71 | p < 0.05 | 187.58 ± 22.82 | n.s |
3 | MIP-3β | 178.38 ± 24.48 | 320.74 ± 11.59 | p < 0.01 | 283.41 ± 34.49 | p < 0.05 |
4 | IL-17 | 3.12 ± 0.37 | 8.16 ± 1.56 | p < 0.01 | 3.33 ± 0.89 | n.s |
5 | MIG | 112.85 ± 42.23 | 690.56 ± 159.29 | p < 0.01 | 146.93 ± 29.25 | n.s |
6 | MIP-1α | 46.67 ± 7.3 | 95.7 ± 10.46 | p < 0.01 | 42.61 ± 4.72 | n.s |
7 | TARC | 29.73 ± 3.86 | 132.74 ± 31.44 | p < 0.01 | 43.26 ± 6.11 | n.s |
8 | IL-5 | 4.75 ± 1.59 | 23.37 ± 3.52 | p < 0.001 | 18.5 ± 0.94 | p < 0.01 |
9 | IL-1α | 23.77 ± 9.04 | 113.51 ± 17.61 | p < 0.001 | 51.19 ± 7.54 | n.s |
10 | TNFα | 2.16 ± 0.83 | 12.25 ± 1.44 | p < 0.001 | 2.67 ± 1.56 | n.s |
11 | TIMP-1 | 1627.59 ± 330.01 | 4850.59 ± 707.44 | p < 0.001 | 1611.3 ± 190.79 | n.s |
12 | MCP-5 | 196.13 ± 14.01 | 1112.96 ± 140.57 | p < 0.0001 | 672.18 ± 64 | p < 0.01 |
13 | G-CSF | 378.82 ± 213.87 | 12,031.13 ± 1317.17 | p < 0.0001 | 7820.85 ± 1429.67 | p < 0.001 |
14 | IFNγ | 1.07 ± 0.26 | 6.88 ± 1.04 | p < 0.0001 | 1.45 ± 0.17 | n.s |
15 | IP-10 | 66.32 ± 6.74 | 190.45 ± 19.34 | p < 0.0001 | 104.05 ± 10 | n.s |
16 | MIP-1β | 61.82 ± 10.59 | 161.69 ± 4.78 | p < 0.0001 | 64.12 ± 10.51 | n.s |
17 | IL-16 | 1957.48 ± 396.85 | 935.04 ± 162.28 | n.s | 429.42 ± 86.09 | p < 0.01 |
18 | MIP-3α | 80.5 ± 23.53 | 206.4 ± 44.29 | n.s | 343.82 ± 55.68 | p < 0.01 |
19 | EPO | 246.74 ± 32.09 | 340.36 ± 30.09 | n.s | 791.16 ± 110.13 | p < 0.001 |
20 | Eotaxin | 826.05 ± 160.13 | 1472.6 ± 361.65 | n.s | 1357.4 ± 222.35 | n.s |
21 | GM-CSF | 3.96 ± 1.67 | 6.76 ± 3.06 | n.s | 2.24 ± 1.09 | n.s |
22 | IL-1β | 3.79 ± 0.45 | 3.81 ± 0.53 | n.s | 2.85 ± 0.69 | n.s |
23 | IL-2 | 3.25 ± 0.8 | 6.16 ± 2.31 | n.s | 2.04 ± 0.95 | n.s |
24 | IL-3 | n.d | n.d | n.s | n.d | n.s |
25 | IL-4 | n.d | n.d | n.s | n.d | n.s |
26 | IL-6 | 6.42 ± 3.28 | 26.44 ± 12.7 | n.s | 18.32 ± 7.34 | n.s |
27 | IL-7 | 0.51 ± 0.03 | 1.1 ± 0.64 | n.s | 0.45 ± 0 | n.s |
28 | IL-9 | 6.27 ± 1.33 | 11.23 ± 3.97 | n.s | 5.48 ± 2.08 | n.s |
29 | IL-10 | 5.96 ± 1.9 | 4.3 ± 1.28 | n.s | 2.63 ± 0.84 | n.s |
30 | IL-12p40 | 1.52 ± 1.06 | 2.88 ± 1.18 | n.s | 2.3 ± 1.26 | n.s |
31 | IL-12p70 | 2.47 ± 2.02 | 2.38 ± 1.09 | n.s | 0.82 ± 0.37 | n.s |
32 | IL-13 | 43.27 ± 5.81 | 48.95 ± 10.74 | n.s | 48.22 ± 6.14 | n.s |
33 | IL-15 | 3.84 ± 1.58 | 27.39 ± 13.8 | n.s | 2.54 ± 0.27 | n.s |
34 | KC | 12.45 ± 4.9 | 812.75 ± 408.45 | n.s | 241.88 ± 62.98 | n.s |
35 | LIF | 0.73 ± 0.28 | 0.82 ± 0.31 | n.s | 0.45 ± 0 | n.s |
36 | M-CSF | 7.16 ± 1.83 | 11.87 ± 1.41 | n.s | 7.77 ± 1.55 | n.s |
37 | MIP-2 | 141.3 ± 2.91 | 147.92 ± 2.69 | n.s | 138.06 ± 1.44 | n.s |
38 | RANTES | 19.32 ± 2.81 | 21.6 ± 7.15 | n.s | 22.69 ± 4.77 | n.s |
39 | VEGF | n.d | 0.86 ± 0.32 | n.s | n.d | n.s |
40 | 6Ckine/Exodus 2 | a.d | a.d | n.s | a.d | n.s |
41 | Fractalkine | 201.36 ± 19.64 | 370.76 ± 119.56 | n.s | 250 ± 43.94 | n.s |
42 | IFNβ-1 | 138.23 ± 59.63 | 75.54 ± 9.65 | n.s | 48.13 ± 1.62 | n.s |
43 | IL-11 | 25.75 ± 3.47 | 39.79 ± 11.55 | n.s | 28.57 ± 19.57 | n.s |
44 | IL-20 | 78.37 ± 18.03 | 81.86 ± 11.61 | n.s | 67.13 ± 11.64 | n.s |
Cytokines | 0 Gy Concentrations | 9 Gy d3 veh Concentrations | p Value d3 veh vs. 0 Gy | 9 Gy d7 veh Concentrations | p Value 9 Gy d7 veh vs. 0 Gy | |
---|---|---|---|---|---|---|
1 | M-CSF | 4.39 ± 0.56 | 9.02 ± 0.6 | p < 0.05 | 6.48 ± 1.03 | n.s |
2 | TIMP-1 | 176.41 ± 20.02 | 610.07 ± 152.39 | p < 0.05 | 282.09 ± 53.98 | n.s |
3 | RANTES | 22.74 ± 3.48 | 9.14 ± 2.35 | p < 0.01 | 2.97 ± 1.81 | p < 0.0001 |
4 | GM-CSF | 1.72 ± 0.81 | 18.5 ± 4.01 | p < 0.01 | 0.45 ± 0 | n.s |
5 | LIF | 3.16 ± 0.33 | 16.14 ± 1.82 | p < 0.001 | 4.76 ± 0.42 | n.s |
6 | MCP-1 | 23 ± 5.98 | 97.03 ± 20.24 | p < 0.001 | 15.5 ± 1.63 | n.s |
7 | IL-2 | 30.45 ± 5.16 | 16.05 ± 4.4 | n.s | 5.36 ± 3.96 | p < 0.05 |
8 | IL-4 | 1.73 ± 0.35 | 0.93 ± 0.19 | n.s | 0.27 ± 0.06 | p < 0.05 |
9 | IL-5 | 1.14 ± 0.19 | 0.64 ± 0.23 | n.s | 0.4 ± 0.08 | p < 0.05 |
10 | IL-9 | 123.77 ± 17.15 | 67.88 ± 19.32 | n.s | 24.11 ± 15.9 | p < 0.05 |
11 | IL-13 | 6.2 ± 1.1 | 3.58 ± 0.7 | n.s | 2.04 ± 0.27 | p < 0.05 |
12 | MIP-1β | 49 ± 7.27 | 45.38 ± 9.36 | n.s | 17.61 ± 2.29 | p < 0.05 |
13 | MDC | 14.12 ± 1.38 | 6.92 ± 2.54 | n.s | 5.29 ± 0.97 | p < 0.05 |
14 | Eotaxin | 324.26 ± 15.66 | 346.38 ± 101.8 | n.s | 34.57 ± 21.06 | n.s |
15 | G-CSF | 2.02 ± 0.22 | 4.89 ± 1.69 | n.s | 2.92 ± 0.5 | n.s |
16 | IFNγ | 4.55 ± 0.53 | 3.75 ± 1.14 | n.s | 4.18 ± 0.8 | n.s |
17 | IL-1α | 121.84 ± 13.94 | 96.47 ± 12.64 | n.s | 81.4 ± 6.21 | n.s |
18 | IL-1β | 15.91 ± 2.34 | 11.06 ± 2.21 | n.s | 8.28 ± 0.27 | n.s |
19 | IL-3 | b.d | b.d | n.s | b.d | n.s |
20 | IL-6 | 3.6 ± 0.14 | 5.83 ± 1.74 | n.s | 4.86 ± 0.58 | n.s |
21 | IL-7 | 10.41 ± 2.52 | 6.26 ± 1.71 | n.s | 3.13 ± 1.23 | n.s |
22 | IL-10 | 47.89 ± 2.93 | 27.25 ± 6.85 | n.s | 26.5 ± 2.31 | n.s |
23 | IL-12p40 | 11.11 ± 2.34 | 5.21 ± 1.52 | n.s | 10.88 ± 2.03 | n.s |
24 | IL-12p70 | b.d | b.d | n.s | b.d | n.s |
25 | IL-15 | 47.12 ± 10.27 | 22.24 ± 5.35 | n.s | 16.72 ± 4.65 | n.s |
26 | IL-17 | 16.82 ± 4.53 | 16.67 ± 4.94 | n.s | 2.35 ± 1.26 | n.s |
27 | IP-10 | 37.03 ± 4.84 | 50.28 ± 14.45 | n.s | 5.37 ± 3.34 | n.s |
28 | KC | 41.05 ± 3.5 | 43.7 ± 14.93 | n.s | 16.55 ± 3.56 | n.s |
29 | MIG | 715.16 ± 171.53 | 1302.87 ± 524.66 | n.s | 106.75 ± 74.75 | n.s |
30 | MIP-1α | 25.79 ± 4.29 | 45.27 ± 6.09 | n.s | 25.08 ± 3.46 | n.s |
31 | MIP-2 | 215.85 ± 25.28 | 175.98 ± 25.08 | n.s | 160.72 ± 13.27 | n.s |
32 | TNFα | 2.95 ± 0.86 | 4.88 ± 1.46 | n.s | 0.88 ± 0.3 | n.s |
33 | VEGF | 35.16 ± 7.69 | 17.33 ± 6.47 | n.s | 38.02 ± 4.49 | n.s |
34 | 6Ckine/Exodus 2 | 1246.48 ± 159.41 | 4785.37 ± 3818.81 | n.s | 821.86 ± 239.75 | n.s |
35 | EPO | 93.9 ± 35.11 | 37.71 ± 21.7 | n.s | 147.72 ± 34.56 | n.s |
36 | Fractalkine | 938.65 ± 115.42 | 520.75 ± 171.04 | n.s | 529.81 ± 103.02 | n.s |
37 | IFNβ-1 | 252.83 ± 44.12 | 92.82 ± 19.95 | n.s | 318.49 ± 72.79 | n.s |
38 | IL-11 | 631.25 ± 124.99 | 193.75 ± 49.54 | n.s | 785.42 ± 195.99 | n.s |
39 | IL-16 | 640.47 ± 93.76 | 387.31 ± 118.71 | n.s | 334.19 ± 33.16 | n.s |
40 | IL-20 | 39.94 ± 4.59 | 21.38 ± 2.34 | n.s | 38.9 ± 7.28 | n.s |
41 | MCP-5 | 126.93 ± 14.83 | 447.78 ± 156.78 | n.s | 204 ± 35.6 | n.s |
42 | MIP-3α | 5.11 ± 0.94 | 2.39 ± 0.31 | n.s | 9.17 ± 2.05 | n.s |
43 | MIP-3β | 76.22 ± 10.04 | 90.66 ± 19.28 | n.s | 84.96 ± 9.44 | n.s |
44 | TARC | 21.57 ± 2.48 | 59.78 ± 23.06 | n.s | 8.88 ± 0.63 | n.s |
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Cui, W.; Hull, L.; Zizzo, A.; Wang, L.; Lin, B.; Zhai, M.; Xiao, M. Pharmacokinetic Study of rhIL-18BP and Its Effect on Radiation-Induced Cytokine Changes in Mouse Serum and Intestine. Toxics 2023, 11, 35. https://doi.org/10.3390/toxics11010035
Cui W, Hull L, Zizzo A, Wang L, Lin B, Zhai M, Xiao M. Pharmacokinetic Study of rhIL-18BP and Its Effect on Radiation-Induced Cytokine Changes in Mouse Serum and Intestine. Toxics. 2023; 11(1):35. https://doi.org/10.3390/toxics11010035
Chicago/Turabian StyleCui, Wanchang, Lisa Hull, Alex Zizzo, Li Wang, Bin Lin, Min Zhai, and Mang Xiao. 2023. "Pharmacokinetic Study of rhIL-18BP and Its Effect on Radiation-Induced Cytokine Changes in Mouse Serum and Intestine" Toxics 11, no. 1: 35. https://doi.org/10.3390/toxics11010035