Enhancement of Cytotoxicity of Active Macrophages by Mycoplasma: Role of Mycoplasma‐Associated Induction of Tumor Necrosis Factor‐α (TNF‐α) in Macrophages

Abstract

Tumor necrosis factor-alpha (TNF-a)-inducing activity of several mycoplasmas including Mycoplasma pneumoniae, a causative agent in human respiratory infectious diseases, was investigated. Purified peritoneal macrophages from BALB/c mice markedly enhanced their cytotoxic activity to Meth A cells, when cultured with either viable or non-viable mycoplasmas. The supernatants of the macrophage culture with mycoplasmas, M. pneumoniae and Acholeplasma laidlawii, showed the potent cytotoxic activity to TNF-a-sensitive L cells but not to TNF-a-insensitive L cells. Addition of anti-TNF-a antiserum inhibited completely the cytotoxic activity of these supernatants, indicating that a major part of the cytotoxic activity might be due to TNF-a. Various other mycoplasmas, either glucose-or arginineutilizing species, as far as tested showed also the potent activity to produce TNF-a. These results strongly suggest the possibility that mycoplasmas possess the activity of TNF-a induction which might be responsible for a part of enhancement of cytotoxic activity of macrophages and resistance to infection with mycoplasmas in vivo.Mycoplasmas have been isolated from almost all domestic and laboratory animals and man, and often cause the mycoplasma diseases such as respiratory infections and others. In humans, Mycoplasma pneumoniae is the causative agent of upper respiratory tract infections and pneumonia (14). These microorganisms lack the specific cell wall components of bacteria, such as diaminopimelic and muramic acids, and exist predominantly in an extracellular environment in close association with the cell plasma membrane (5). Although mycoplasmas can cause minimal morphological changes in mycoplasma-infected cell cultures, the possible simultaneous effects are numerous, in mycoplasma-infected immunocytes, such as lymphocytes, macrophages, and hybridoma cell lines, including enhancement of productions of immunoglobulin (26), cytokines (23), and interferon (4, 10, 24). Furthermore, the cytotoxicity of macrophages (17,20) and natural killer (NK) cells (7,18) to target cells are enhanced, when these cell lines were contaminated with mycoplasmas. Although the mechanisms of enhancement of macrophages-mediated 231

Induction of Cytokines in Human Peripheral Blood Mononuclear Cells by Mycoplasmas

“…Moreover, it was reported that TNF-a was induced by a various species of mycoplasmas by a protein kinase C-independent pathway (2,22,23,25). Our results were coincident with these.…”

Mycoplasma pneumoniae as an Under- Recognized Agent of Vasculitic Disorders

“…These inflammatory substances include interleukin-8, tumor necrosis factor-, macrophage inflammatory peptide-1 [Hardy et al, 2001], intercellular adhesion molecule-1 [Krunkosky et al, 2007], and regulated upon activation, normal T cells expression and secreted [Dakhama et al, 2003], among others. Tumor necrosis factor-has been observed to be induced by M. pneumoniae in vitro from an early period of investigation [Arai et al, 1990;Kita et al, 1992]. This cytokine, along with interleukin-8, must play a pivotal role in eliciting vasculitic/thrombotic vascular occlusion.…”

Molecular Biology and Pathogenicity of Mycoplasmas

“…The number of GAA repeats ranges from 10 to 16 (27). Genetic analysis of phenotypically switched clonal isolates, representing the ON or OFF expression state of the pMGA product from a number of pMGA genes in M. gallisepticum R, revealed that expressible pMGA genes always contained a (GAA) 12 motif. Different numbers of the GAA repeats were correlated with the OFF expression state of the pMGA (159).…”

“…How does the (GAA) 12 motif function to initiate pMGA transcription? An intriguing model proposed by Glew (159) suggests that the (GAA) 12 motif serves as a linker or a spacer for two flanking binding sites necessary for the initiation of pMGA transcription. The first binding site, localized downstream of the (GAA) 12 motif, is a well-defined promoter site for RNA polymerase.…”

“…An intriguing model proposed by Glew (159) suggests that the (GAA) 12 motif serves as a linker or a spacer for two flanking binding sites necessary for the initiation of pMGA transcription. The first binding site, localized downstream of the (GAA) 12 motif, is a well-defined promoter site for RNA polymerase. The second site, upstream of the (GAA) 12 motif, contains a region of sequence homology present in all known pMGA genes.…”