Phospholipids and reactive nitrogen intermediates collaborate in expression of the T cell mitogenesis-inhibitory activity of immunosuppressive macrophages induced in mycobacterial infection

Abstract

SUMMARYWe studied the role of phospholipids and nitric oxide in expression of the suppressor activity of splenic macrophages induced by Mycobacterium avium-intracellulare complex infection (MAICinduced macrophages) in mice against mitogenic response of concanavalin A (Con A)-stimulated splenocytes (SPC) as follows. First, phosphatidylserine (PS) and phosphatidylinositol were found to suppress Con A-induced mitogenesis of SPC via inhibition of IL-2 production and acquisition of IL-2 reactivity in Con A-stimulated T cells. The mitogenesis-inhibitory activity of PS was increased when SPC were cultured under mildly acidic condition (pH 6 . 3). When SPC were pretreated with PS for 24 h prior to Con A blastogenesis, their mitogenic response was irreversibly abrogated. Second, N G -monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthase, was found to attenuate in part the expression of the suppressor activity of MAIC-induced macrophages. Third, reactive nitrogen intermediates (RNI) including NO generated from acidified NO ÿ 2 exerted potent inhibitory activity against SPC mitogenic response, and the suppressive activity of RNI was significantly augmented by the combination with PS. These findings indicate that phospholipids and RNI play an important role in the expression of suppressor activity of MAIC-induced macrophages as the effector molecules.

Comparative studies on the roles of mediator molecules in expression of the suppressor activity ofMycobacterium aviumcomplex-induced immunosuppressive macrophages against T cell and B cell mitogenic responses

“…We previously found that RNIs, free fatty acids (such as arachidonic acid), TGF-β, PGE 2 and phosphatidylserine inhibited T cell mitogenesis in a significant manner, thereby suggesting that these factors play roles as the suppressor mediators of MAC-MΦs [11][12][13]. Therefore, we next compared the susceptibilities of T cell and B cell mitogenesis to these suppressor mediators.…”

“…In order to understand the role of RNIs, important mediators of suppressor M Φs [12,13,21,25,26], in the expression MAC-MΦ's suppressor activity against B cell mitogenesis, we compared the effects of L-NMMA on the MAC-MΦ-mediated suppression of the proliferative responses of SPCs to Con A and LPS stimulation. As indicated in Fig.…”

“…MAC-M Φ s were found to strongly down-regulate IL-2 receptor expression by Con Astimulated T cells and moderately reduced the IL-2 production of the T cells [9,10]. It has also been found that the suppressor activity of MAC-M Φ s is mediated by humoral mediators, including reactive nitrogen intermediates (RNIs), transforming growth factor-β (TGF-β ), free fatty acids, phosphatidylserine and prostaglandin E 2 (PGE 2 ), which are produced by MAC-M Φ s responding to Con A stimulatory signals and some kinds of immunopotentiating cytokines, especially IFN-γ and TNF-α [11][12][13]. Recently, we have elucidated that the B7-1-like molecule-mediated cell contact of MAC-M Φ s with target T cells is required for the efficacious manifestation of MAC-M Φ 's suppressor activity [14] and that the MAC-M Φ -derived suppressor signals cross-talk with the early signalling events before the activation of protein kinase C and/or intracellular calcium mobilization [15].…”

Opposite effects of M. leprae or M. bovis BCG delipidation on cellular accumulation into mouse pleural cavity. Distinct accomplishment of mycobacterial lipids in vivo

“…BCG, Moureau strain, was obtained from the Ataulpho de Paiva Foundation, Rio de Janeiro, Brazil. The number of mycobacteria used in all assays was 8 ¥10 6 bacilli as described in the literature [9,10,12].…”

“…Defective macrophage presentation would be responsible for the incapacity of lepromatous leprosy cells to respond to M. leprae [3]. In fact, the knowledge about inflammatory reactions in mycobacterial infections claims further advances [7][8][9][10]. Mycobacteria mediate mechanisms of escape within macrophages [8].…”