The immune environment of human soft-tissue injury is unstudied. We studied fracture soft-tissue hematomas (FxSTH) in 56 patients with high-energy bony fractures. FxSTH serum and mononuclear cells (MNC) as well as fracture patient plasma and blood MNC were studied. Twenty healthy controls donated plasma and MNC. Soluble tumor necrosis factor (TNF)-alpha, interleukin (IL-1 beta, IL-2, 6, 8, 10, 12, and interferon-gamma were studied by enzyme linked immunosorbent assay. Cells were studied by flow cytometry after cell-membrane stains for CD-14, TNF-alpha (mTNF), and human leukocyte antigen-DR, or intracellular stains for TNF (icTNF) and IL-10. Thirty-six patients with Injury Severity Score < 15 were analyzed further to evaluate the effects of isolated fracture on systemic immunity. Cytokines were rarely detectable in control plasma. TNF-alpha, IL-1 beta, IL-2, and interferon-gamma were rarely found in FxSTH serum or fracture patient plasma. All FxSTH sera were rich in IL-6, peaking before 48 hours (12,538 +/- 4,153 vs. 3,494 +/- 909 pg/mL, p = 0.02, U test). In Injury Severity Score < 15, IL-6 was not detectable in most early fracture patient plasma, but rose after 48 hours (p = 0.028). FxSTH serum IL-8 peaked after 48 hours (440 +/- 289 vs. 4,542 +/- 1,219 pg/mL, p = 0.006) and circulating IL-8 appeared after 72 hours. IL-6 and IL-8 showed gradients from FxSTH serum to paired PtS (p < 0.05, Wilcoxon). IL-10 was abundant (884 +/- 229 pg/mL) in FxSTH serum < 24 hours old. FxSTH serum IL-12 peaked late (3,323 +/- 799 pg/mL, day 4-7) then fell (p < 0.001, analysis of variance). Only IL-12 was higher in fracture patient plasma (1,279 +/- 602 pg/mL) than FxSTH serum (591 +/- 327 pg/mL) during the first 48 hours (p = 0.032, U test). On flow cytometry, control monocytes expressed 201 +/- 31 mTNF sites/cell, but icTNF was absent. mTNF was up-regulated after injury more in FxSTH monocytes (3,202 +/- 870 sites/cell) than peripheral blood monocytes (584 +/- 186 sites/cell) (p < 0.05 vs. peripheral blood monocytes by Wilcoxon, p < 0.001 vs. control monocytes by U test). Intracellular IL-10 was abundant in all MNC, but varied widely after injury. Fracture and peripheral blood monocytes expressed far less human leukocyte antigen-DR than control monocytes. Fractures create an inflammatory local environment. Proximal mediators are cell-associated and relatively confined to the wound, but soluble IL-6, IL-8, and IL-10 are abundant and probably exported. Systemic MNC have complex responses to local injuries. These may reflect the combined impact of multiple soluble cytokines initially generated within the wound. FxSTH appear to be a potentially important source of immunomodulatory cytokines in trauma.

NK cell function is regulated by cytokines and certain biochemical mediators in a positive or negative manner. This study was performed to investigate the suppressive effects of PGE2 on IL-15-activated human NK cell function. Purified NK cells were cultured with 200 ng/ml IL-15 for 2 days in the presence or absence of 10–200 ng/ml PGE2. PGE2 significantly suppressed NK cell-mediated cytotoxicity and IFN-γ production at the secretional and the transcriptional levels. We also evaluated the effect of PGE2 on the IL-15R complex that consists of IL-2Rβ, common γ-chain (γc-chain), and a specific chain IL-15Rα. Percentage of positive cells and number of binding sites for γc-chain were significantly increased after IL-15 treatment; however, a substantial decrease was observed with PGE2 cotreatment. In contrast, constitutive expression of IL-2Rβ was significantly decreased after IL-15 treatment, with no change detected in the presence of PGE2. At the transcriptional level, neither IL-15 nor PGE2 had significant effects on the expression of β- or γc-chains. There was a 3-fold increase in the expression of IL-15Rα at the transcriptional level that peaked at 8 h after IL-15 treatment; however, PGE2 had no significant effect. Suppression of NK function by PGE2 was not due to the endogenous production of IL-4, IL-10, or TGF-β1 by NK cells. These results suggest that down-regulation of surface expression of γc-chain on NK cells may be one mechanism through which PGE2 mediates suppression of IL-15-activated NK cell function.

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To determine whether B or T lymphoid malignancies could be induced following the exposure of lymphoid cells within different lymphoid organs to a potential chemical carcinogen, 3-methylcholanthrene (3-MC) was directly injected into surgically exposed Peyer's patches (PP), mesenteric lymph nodes (MLN), axillary lymph nodes (ALN) or spleens (SP) of Copenhagen rats. A high incidence of lymphoproliferative disorders was observed within rats which received 3-MC injections into the PP, but not in MLN, ALN or SP injected groups of rats. In addition to the PP environment, the dose of 3-MC and exposure to pristane were important factors in the induction of T versus B cell disorders. Whereas the B cell diseases were observed in pristane-treated rats which also received PP injections of low doses (5 or 50 micrograms) of 3-MC, in animals receiving a higher dose (500 micrograms) a much higher incidence of T cell disorders was detected. The observed lymphoproliferative diseases were categorized as B lymphocytic leukemias, B lymphomas or thymic lymphomas on the basis of histological examination of the tissues, white blood cell numbers and differentials, and the morphological and phenotypic characteristics of cell isolates. Abnormal DNA staining characteristics, increased soft agar cloning frequencies and metastasis of the leukemia or tumor cells indicated that malignant cells were associated with the proliferative diseases. Collectively the data indicate that primary lymphoid malignancies of either B or T cell origins may be preferentially and reproducibly induced by localizing low or high doses respectively, of 3-MC within the PP of rats exposed to pristane. These results suggest that PP may have a possible role in the carcinogenesis of lymphocytes following the exposure to chemical carcinogens via the gastrointestinal tract.

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