prostaglandin-d2 and Myeloproliferative-Disorders

Pruritus is a common symptom in patients with Philadelphia chromosome-negative myeloproliferative disorders (MPDs). The pathophysiology of MPD-associated pruritus is unclear. We have demonstrated that MPD mast cells (MCs) are involved by the malignant process. In the present study, we explored the hypothesis that MCs play an important role in the development of pruritogenesis in MPDs. We found that MPD MCs released significantly greater amounts of pruritogenic factors, including histamine, leukotrienes, and interleukin-31 (IL-31) than normal MCs. Elevated levels of IL-31 were also observed in MPD CD3(+) cell-conditioned media. MPD MCs exhibited increased migratory behavior in response to stem cell factor or interleukin-8, which was associated with increased filamentous-actin content. Furthermore, the presence of pruritus in MPDs was statistically correlated with a greater number of MCs being generated by CD34(+) cells, a greater number of MC colonies being formed by CD34(+) cells, decreased apoptosis and prostaglandin D(2) release by cultured MCs, and higher plasma levels of IL-31. These data demonstrate that functional abnormalities of MPD MCs probably lead to pruritogenesis in patients with MPDs. These studies provide cellular and molecular targets for the development of antipruritus drugs for patients with MPDs.

Topics: Actins; Alleles; Cell Movement; Histamine; Humans; Interleukin-4; Interleukins; Janus Kinase 2; Leukotrienes; Mast Cells; Myeloproliferative Disorders; Nerve Growth Factor; Prostaglandin D2; Tryptases

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Blood Platelet Disorders; Blood Platelets; Female; Humans; Myeloproliferative Disorders; Pancreatic Neoplasms; Platelet Aggregation; Prostaglandin D2; Prostaglandins D

NADP-linked 15-hydroxyprostaglandin dehydrogenase for prostaglandin D2 (PGD2DH) transforms prostaglandin D2 (PGD2) to inactive 15-keto-PGD2. This enzyme activity was spectrophotometrically determined in the cytosol of platelets and platelet sensitivities to PGD2 were studied in patients with myeloproliferative disorders (MPD) as well as in normal subjects. Platelet sensitivities to exogenous and endogenous PGD2 were estimated by IC50 of added PGD2 for platelet aggregation and by the inhibitory effect of a specific thromboxane synthetase inhibitor (OKY-046) on collagen-induced aggregation, respectively. PGD2DH activities of MPD patients were significantly higher than those of normal subjects (p less than 0.01). Although decreased sensitivity to exogenous PGD2 was detected in some MPD patients, they were not always associated with the increased enzyme activities. Furthermore, no specific correlation was found between PGD2DH activities and the inhibitory effects of OKY-046. Thus, PGD2DH seems to have little effect on the action of PGD2 against platelet aggregation in MPD patients and normal subjects.

Topics: Adult; Age Factors; Aged; Blood Platelets; Female; Humans; Hydroxyprostaglandin Dehydrogenases; Male; Middle Aged; Myeloproliferative Disorders; NADP; Platelet Aggregation; Prostaglandin D2; Prostaglandins D; Sex Factors

Topics: Acute Disease; Epoprostenol; Humans; In Vitro Techniques; Leukemia; Myeloproliferative Disorders; Platelet Aggregation; Prostaglandin D2; Prostaglandins D