Interleukin-1 (IL-1) and interleukin-6 (IL-6), powerful stimulants of the hypothalamic-pituitary-adrenal (HPA) axis, increase in response to whole body exercise. Strenuous inspiratory resistive breathing (IRB), a form of clinically relevant "exercise" for the respiratory muscles, produces -endorphin through a largely unknown mechanism. We investigated (in 11 healthy humans) whether strenuous IRB produces proinflammatory cytokines and -endorphin in parallel with stimulation of the HPA axis, assessed by concurrent measurement of ACTH. Subjects underwent either severe [at 75% of maximal inspiratory pressure (P_{m max})] or moderate (at 35% of P_{m max}) IRB. Plasma cytokines, -endorphin, and ACTH were measured at rest (point R), at the point at which the resistive load could not be sustained (point F), and at exhaustion [15 min later (point E)]. During severe IRB, IL-1 increased from 0.83 ± 0.12 pg/ml at point R to 1.88 ± 0.53 and 4.06 ± 1.27 pg/ml at points F and E, respectively (P < 0.01). IL-6 increased from 5.30 ± 1.02 to 10.33 ± 2.14 and 11.66 ± 2.29 pg/ml at points F and E, respectively (P = 0.02). ACTH and -endorphin fluctuated from 20.87 ± 5.49 and 25.03 ± 3.97 pg/ml at point R to 22.97 ± 4.41 and 26.32 ± 3.93 pg/ml, respectively, at point F and increased to 46.96 ± 8.55 and 40.32 ± 5.94 pg/ml, respectively, at point E (P < 0.01, point E vs. point F). There was a positive correlation between the IL-6 at point F and the ACTH and -endorphin at point E (r = 0.88 and 0.94, respectively; P < 0.01) as well as between the increase in IL-6 (between points R and F) and the increases in ACTH and -endorphin (between points F and E, r = 0.91 and 0.92, respectively; P < 0.01). Moderate IRB did not produce any change. We conclude that severe IRB produces proinflammatory cytokines and stimulates the HPA axis in humans secondary to the production of cytokines (especially IL-6).