A paracrine role for chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2) in mediating chemotactic activation of CRTH2⁺ CD4⁺ T helper type 2 lymphocytes

Abstract

Activation of human CRTH2(+) CD4(+) T helper type 2 (Th2) cells with anti-CD3/anti-CD28 led to time-dependent production of prostaglandin D(2) (PGD(2)) which peaked at 8 hr. The production of PGD(2) was completely inhibited by cotreatment with the cyclo-oxygenase inhibitor diclofenac (10 microm) but was not affected by cotreatment with ramatroban, a dual antagonist of both the thromboxane-like prostanoid (TP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Supernatants from activated CRTH2(+) CD4(+) Th2 cells caused a concentration-dependent increase in the migration of naive CRTH2(+) CD4(+) Th2 cells compared to supernatants from unstimulated CRTH2(+) CD4(+) Th2 cells. The level of chemotactic activity peaked at 8 hr after activation, corresponding to the peak levels of PGD(2), but production of chemotactic activity was only partially inhibited by the cyclo-oxygenase inhibitor diclofenac. In contrast, ramatroban completely inhibited the chemotactic responses of naive Th2 cells to supernatants from activated CRTH2(+) CD4(+) Th2 cells collected up to 8 hr after activation, although supernatants collected 24 hr after activation were less sensitive to inhibition by ramatroban. The selective TP antagonist SQ29548 did not inhibit migration of Th2 cells, implicating CRTH2 in this response. These data suggest that CRTH2 plays an important paracrine role in mediating chemotactic activation of Th2 cells. Interestingly, although PGD(2) is produced from Th2 cells and contributes to this paracrine activation, it appears that additional CRTH2 agonist factors are also produced by activated Th2 cells and the production of these factors occurs independently of the cyclo-oxygenase pathway of the arachidonic acid metabolism.

Novel Function of CRTH2 in Preventing Apoptosis of Human Th2 Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

“…P rostaglandin D 2 is the major prostanoid released from mast cells (1) and is also produced in substantial quantities by Th2 lymphocytes (2,3). It has been detected in high concentrations at sites of allergic inflammation and mediates its effects through high affinity interactions with D prostanoid receptor (DP) 2 1 (2) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2; also named DP 2 ).…”

“…ϩ CD4 ϩ Th2 cells were prepared using a modified method described previously (3). Briefly, PBMC were isolated from buffy coats from healthy blood donors whose atopic status was unknown (National Blood Service, Bristol, U.K.) by Ficoll Hypaque (Amersham Biosciences) density gradient centrifugation, followed by CD4 ϩ cell purification using MACS CD4 ϩ T cell isolation kit II (Miltenyi Biotec).…”

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

“…It has been reported that activated Th2 cells are able to produce PGD 2 (7,8). To understand whether the enhancing effect of cysLTs is mediated by a secondary production of PGD 2 by Th2 cells, we examined the effect of diclofenac, a cyclooxygenase inhibitor, on cytokine production induced by LTE 4 (Fig.…”

“…PGD 2 , produced by the activity of the cyclooxygenase enzymes, is the major prostanoid released from mast cells during an allergic response (3,4), although macrophages (5), dendritic cells (6), and CD4 + Th2 lymphocytes (7,8) may contribute to PGD 2 production in some circumstances. A significant contribution of PGD 2 to the development of allergic inflammation has been suggested by the observations of enhanced eosinophilic lung inflammation and cytokine release in transgenic mice overexpressing PGD 2 synthase (9).…”

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

“…P rostaglandin (PG) D 2 is a product of arachidonic acid metabolism that is secreted predominantly by mast cells [1] but also by T-helper cell (Th) type 2 lymphocytes [2]. Levels of PGD 2 are raised in the airways of patients with asthma after allergen challenge [3], suggesting a role for this prostanoid in promoting Th2-mediated allergic inflammation.…”