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Phospholipase A2 in inflammatory bowel disease
  1. Institute for Clinical Chemistry,
  2. Klinikum Mannheim, University of Heidelberg,
  3. Theodor-Kutzer-Ufer 1–3,
  4. D-68167 Mannheim, Germany
  3. A CHOPRA,
  4. S SAINI
  1. Department of Microbiology and Immunology,
  2. University of Texas Medical Branch,
  3. Galveston,
  4. TX 77555–1019, USA
  5. Department of Internal Medicine
  6. Department of Pathology
  1. Professor Peterson.

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Editor,—Increased release of pro-inflammatory eicosanoids such as prostaglandin E2 and thromboxane B2 from mononuclear cells occurs during relapse in patients with inflammatory bowel disease (IBD).1 The key enzyme in eicosanoid synthesis is phospholipase A2(PLA2). Raised serum concentrations of the PLA2group II isoenzyme can be detected by immunoassay during the acute stages of IBD.2 We read with interest the recent article by Peterson et al about the role of a phospholipase A2 activating protein, PLAP (Gut 1996;39: 698–704). The authors showed clearly that PLAP can be detected in monocytes and granulocytes originating from intestinal mucosa of patients with Crohn’s disease and ulcerative colitis. In addition to this finding, extracellular deposits of PLAP antigen were associated with blood vessels and oedematous fluid from the inflamed tissue. Peterson et al postulated that PLAP may be involved in increasing PLA2 activity with consecutive eicosanoid generation in IBD. We propose a further possible mechanism of PLA2 activation during acute IBD in which the pro-inflammatory cytokine interleukin-6 (IL-6) is a key mediator. Peripheral blood concentrations of this cytokine are raised during acute IBD.3 We showed recently that recombinant human IL-6 alone can increase serum concentrations of PLA2 group II isoenzyme in humans.4 Therefore, we suggest that increased IL-6 concentrations during relapse of IBD are also able to induce PLA2 by a different mechanism from PLA2activation via PLAP. The important role of cytokines in the induction of PLA2 was confirmed by Crowl et al,5 who showed that IL-6 could induce PLA2 in vitro.

The molecular mechanism of this induction was further elucidated by detection of an IL-6 response element in the promoter region of the PLA2 gene.5 In conclusion, activation of PLA2 by PLAP could be a possible mechanism for increased eicosanoid synthesis in IBD but direct induction of PLA2gene transcription by pro-inflammatory cytokines should be taken into account. Therefore, we suggest a study with parallel measurements of IL-6 and PLA2 serum concentrations during acute relapse of IBD to correlate these parameters and to determine the profiles of occurrence of these inflammation markers. We have developed a radiometric assay which may be useful as a sensitive and reliable method for absolute measurements of the true PLA2 group II enzyme activity in serum.6 Parallel measurements using a PLA2 group II immunoassay may also indicate whether activation or inhibitory factors of PLA2 are also present in peripheral blood.



Editor,—The role of cytokines in the formation of lipid mediators involved in cell signalling was recently reviewed, and the interplay among these important substances forms the basis for future development of novel therapeutic approaches for several inflammatory diseases.1-1 The proposed mechanism involving the role of IL-6 in elevating group II secretory PLA2(sPLA2) in the acute stages of IBD would be consistent with the reported stimulatory effects of pro-inflammatory cytokines (for example, IL-6, IL-1, tumour necrosis factor α (TNF-α)) on eicosanoid generation in cells from various tissues.1-1 In murine bone marrow mast cells, IL-10 and IL-1β have been reported to increase expression of type II sPLA2, but not cytosolic PLA2 (cPLA2).1-2 cPLA2and sPLA2 are two isoforms of the enzyme that have been implicated in inflammation.1-3 Arachidonic acid released from membrane phospholipids by the action of PLA2 becomes the substrate for the cyclooxygenase and lipooxygenase enzymes, which synthesise prostaglandins and leuko- trienes, respectively. In human pulmonary epithelial cells, IL-1β, TNF-α, and interferon-γ (IFNγ) cause coordinate induction of both cPLA2 and cyclooxygenase-2 (COX-2) mRNA, resulting in increased prostaglandia E2 (PGE2) release.1-3 In the human rheumatoid synovial fibroblast, PGE2 accumulation in response to IL-1β has been shown to be a direct result of coordinated upregulation of the 85 kDa cPLA2 and COX-2.1-4 1-5 TNF-α treatment of human bronchial epithelial cells results in upregulation of cPLA2 gene expression without an effect on sPLA2 gene expression.1-6In normal tissues, arachidonic acid metabolism is regulated by the limited availability of the arachidonic acid substrate, but recently, IL-4 was shown to downregulate levels of cPLA2 mRNA and COX-2 mRNA in mouse parietal bone cultures.1-7 1-8 Further, transforming growth factor (TGF) beta 2 was shown to reduce sPLA2 mRNA levels in rat mesangial cells treated with cytokines and forskolin.1-9 The complexity of the roles of cytokines and arachidonic acid metabolites in regulating inflammation is further highlighted by the findings that PGE2 can (1) upregulate IL-6 mRNA production, and (2) downregulate TNF-α RNA and protein production in different in vitro and in vivo models.1-10-1-12 As discussed in our recent report, PLAP may participate in the intricate control mechanisms that evoke and modulate the actions of cytokines and arachidonic acid metabolites in IBD and other inflammatory diseases. PLAP has been shown to induce IL-2 synthesis in a murine T helper cell line (EL-4)1-13 and IL-1 and TNF-α production in human monocytes.1-14 The precise role of PLAP in PLA2 type specificity and enzymatic activity, as well as in the molecular mechanism leading to IBD, remains to be elucidated.


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