Figure 5. Low doses of IL-17A induce female-dominant mechanical pain.

(A) PTX (1 μg/ml, 16h) promotes IL-17 release from both female and male peritoneal macrophages in vitro, which is abolished by Il23r^−/− only in females.

(B) IL-23 incubation (100 ng/ml, 16h) induces greater IL-17 release from female peritoneal macrophages than male counterparts in vitro.

(C) I.PL. IL-17A induces mechanical pain in females at 1–100 ng and males only at 100 ng.

(D-E) I.PL. IL-17A at 1–100 ng fails to induce heat hyperalgesia (D) or cold hypersensitivity (D) in either sex.

(F) AUC (0.5–3h) of Fig. 5C showing female-dominant mechanical pain by IL-17A (10 and 100 ng).

(G) Co-I.PL. injection of IL-17A neutralizing antibody or IL-17RA neutralizing antibody (2 μg) with IL-23 (100 ng) abolishes IL-23-induced pain in females.

(H) Clodronate (I.V., 1 mg / 200 μl) does not affect IL-17A-induced pain (I.PL., 10 ng) in females.

(I) IL-17A (I.PL., 100 ng) induces mechanical allodynia in female Il23^−/− mice.

(J) Estrogen deficiency by OVX reduces IL-17A-induced mechanical pain (I.PL., 10 ng) in females.

(K) Androgen deficiency by ORX enables IL-17A-induced pain (I.PL., 10 ng) in males.

(L-M) PTX increases serum IL-17 in both sexes (L) but enhances DRG IL-17 only in females (M) in CIPN (4 x PTX, 2 mg/kg).

Data are mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001; Two-way ordinary ANOVA with Bonferroni’s post hoc test (A and B; L and M); Two-way RM ANOVA with Bonferroni’s post hoc test (C-H); F _{(3, 32)} = 2.575 (A); F _{(1, 24)} = 4.336 (B); F _{(28, 128)} = 8.077 (C); F _{(28, 128)} = 0.5004 (D); F _{(28, 128)} = 0.9792 (E); F _{(3, 32)} = 7.285 (F); F _{(8, 84)} = 7.870 (G); F _{(5, 50)} = 0.2779 (H); F _{(4, 40)} = 0.3429 (I); F _{(5, 40)} = 13.05 (J); F _{(5, 40)} = 10.26 (K); F _{(1, 20)} = 0.7352 (L); F _{(1, 20)} = 5.715 (M).

AUC: Area under curve; PTX: Paclitaxel; I.PL.: Intraplantar; OVX: Ovariectomy; ORX: orchiectomy; BL: Baseline.