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Failed host defense against intracellular Leishmania in absence of SLPI involves imbalance of Th1/Th2 cytokines and M1/M2 polarization linked to dysregulation of SOCS1 and IL‐27. SLPI, a potent epithelial and myeloid‐derived serine protease inhibitor with antimicrobial and anti‐inflammatory functions, is induced by the intracellular parasite Leishmania major, and increased SLPI expression is evident within lesions that follow L. majorinfection. In contrast to self‐resolving infection in C57Bl/6 WT mice, Slpi−/−mice launch a strong Th1 response to L. major, yet fail to control infection and develop destructive, nonhealing lesions with systemic spread of parasites. Because SLPI is both produced by murine macrophages and antagonizes their function, we examined the contribution of macrophage polarization to the defective host response in the absence of SLPI. Slpi−/−and Slpi+/+macrophages were first primed with either IFNγ or IL‐4 to generate classically activated M1 or alternatively activated M2 macrophages. After infection with L. major, Slpi−/−M1 macrophages expressed elevated iNOS RNA, whereas arginase was more highly expressed in WT than Slpi−/−M2 macrophages. After in vivo infection, we found that both IFNγ and iNOS were persistently overexpressed in chronic lesions in Slpi−/−mice, but surprisingly, IL‐4 and arginase concomitantly remained elevated. Moreover, overexpression of the negative regulators SOCS1 and IL‐27 provided insight into the failure of IFNγ to clear L. majorfrom the dermal lesions. Notably, adenoviral delivery of SLPI to L. major‐infected Slpi−/−mice significantly limited the progression of infection. These studies suggest that convergence of M1 and M2 macrophage responses may influence the outcome of innate host defense against intracellular parasites and that SLPI is critical for coordinating resistance to chronic leishmaniasis.

Abnormal nitric oxide (NO) synthesis has been implicated in the pathogenesis of both periodontal disease and diabetes mellitus. In diabetic patients, increased inducible NO synthase in inflamed gingiva correlated with NO in gingival crevicular fluid. Although increased NO reflected more-severe inflammation, it was associated with reductions in CFU of Prevotella intermedia, a major periodontopathogen, highlighting dual roles for NO.

ABSTRACTAbnormal nitric oxide (NO) synthesis has been implicated in the pathogenesis of both periodontal disease and diabetes mellitus. In diabetic patients, increased inducible NO synthase in inflamed gingiva correlated with NO in gingival crevicular fluid. Although increased NO reflected more-severe inflammation, it was associated with reductions in CFU of Prevotella intermedia, a major periodontopathogen, highlighting dual roles for NO.

Innate and adaptive immunity function to eliminate foreign invaders and respond to injury while enabling coexistence with commensal microbes and tolerance against self and innocuous agents. Although most often effective in accomplishing these objectives, immunologic processes are not fail‐safe and may underserve or be excessive in protecting the host. Checks and balances to maintain control of the immune system are in place and are becoming increasingly appreciated as targets for manipulating immunopathologic responses. One of the most recognized mediators of immune regulation is the cytokine transforming growth factor‐β (TGF‐β), a product of immune and nonimmune cells. Emerging data have unveiled a pivotal role for TGF‐β as a perpetrator of suppression by CD4+CD25+regulatory T (Treg) cells and in apoptotic sequelae. Through its immunosuppressive prowess, TGF‐β effectively orchestrates resolution of inflammation and control of autoaggressive immune reactions by managing T cell anergy, defining unique populations of Treg cells, regulating T cell death, and influencing the host response to infections.

Purpose:An undetermined number of patients with temporomandibular joint (TMJ) symptoms have been treated with intra-articular disc implants composed of Teflon ethylene/propylene or Teflon polytetrafluoroethylene and aluminum oxide (Proplast-Teflon; Vitek, Houston, TX). These implants have shown the potential to fragment in situ resulting in nonbiodegradable particles that stimulate a giant cell reaction and lead to degeneration of local structures, pain, and limitation of mandibular opening. We examined the possible relationship between TMJ implants and persistent pain, responses to sensory stimuli, quality of life, and systemic immune dysfunction. Patients and Methods:This case series (32 patients) were referred from university-based orofacial pain centers and private practices from across the United States. Laboratory and clinical assessments evaluated orofacial pain symptoms, neurologic function, clinical signs and symptoms of rheumatologic disease, physical function, systemic measures of immune function, and behavioral measures. Results:We found that TMJ implant patients appeared to have altered sensitivity to sensory stimuli, a higher number of tender points with a diagnosis of fibromyalgia, increased self-report of chemical sensitivity, higher psychologic distress and significantly lower functional ability. Systemic illness or autoimmune disease was not evident in this series of TMJ implant patients. Conclusions:Significant problems were noted on clinical assessment of TMJ implant patients. This is a US government work. There are no restrictions on its use. J Oral Maxillofac Surg 60:1389-1399, 2002

To investigate the ability of hemoglobin (Hgb), a nitric oxide (NO) scavenger, to deplete excess NO and reduce inflammation and injury in synovial tissue from joints with inflammatory arthritis. The severity of streptococcal cell wall– induced arthritis was monitored following administration of Hgb. Plasma nitrite and nitrate levels were measured, and inducible NO synthase (iNOS) and cytokine messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) and joint tissue were evaluated. Following systemic administration of Hgb to arthritic rats, plasma levels of nitrite and nitrate as well as iNOS mRNA expression in the joints and PBMC were significantly reduced. Moreover, inflammatory cell accumulation and disease pathology in the joint tissue were dramatically attenuated without obvious side effects. Consistent with this reduction in the inflammatory response, cytokine gene expression was decreased in the synovium of Hgb-treated rats. Modulation of NO levels through the use of a NO scavenger, Hgb, influences the development and severity of arthritis. These findings suggest that depletion of excess NO by NO scavengers provides a prototype for further exploration of potential treatments for chronic arthritis.

Transforming growth factor beta 1 (TGF-β1) and its closely related homologue, TGF-β2, rapidly induce growth factor gene expression by freshly isolated human peripheral blood monocytes. Within 3 h of exposure to TGF-β, mRNA species specific for interleukin-1 (IL-1β), tumor necrosis factor-α (TNF-α), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were observed. By 14-18 h, cytokine bioactivity and protein were detected in the culture supernatants. Furthermore, not only TGF-β1, but also TGF-β2 mRNA are expressed constitutively in unstimulated monocytes. However, in response to exogenous TGF-β (βl or β2), only TGF-β1 gene expression is upregulated, and the expression of TGF-β2 mRNA is unchanged. This selective autoinduction of TGF-β1 appears to be controlled at both transcriptional and post-transcriptional levels. These paracrine and autocrine activities of TGF-β suggest potential mechanisms through which an inflammatory response can be initiated and amplified. In addition, the TGF-β enhancement of growth factor generation may promote fibrosis and angiogenesis relevant to physiological tissue repair as well as pathological fibrotic sequelae.

A wide variety of functions, many of which represent opposing activities, have been attributed to TGF‐β, a molecule implicated in embryogenesis, development, and immune and inflammatory processes. This paradoxical behavior of promoting or inhibiting cell growth and function, while important in normal physiology and homeostasis, can contribute to or interrupt pathologic sequelae, making TGF‐βa particularly intriguing molecule for study. New transgenic mouse models displaying targeted alterations in TGF‐β1 expression offer novel and unique opportunities to determine the essential function(s) of TGF‐β. J. Leukoc. Biol.55: 401–409; 1994.

Since certain functions mediated by nitric oxide (NO) decline with age, the age dependence of NO production by macrophages fromBALB/c mice was investigated. Lipopolysaccharide-, peptidoglycan- polysaccharide-, or interferon-γ-stimulated splenic and peritoneal macrophages from young (1 month old), middle-aged (4–5 months old), and old (6–20 months old) BALB/c mice showed a progressive and marked decline in NO production. This age-related decline in inducible NO extended to C57/BL6 and CB6F1 mice. mRNA for inducible NO synthase (iNOS), the enzyme responsible for inducible NO production by macrophages, also declined with age. Importantly, the reduced NO production by macrophages from old mice could be up-regulated by pretreating the mice with either cholera toxin or concanavalin A. These findings indicate that reduced production of NO by murine macrophages correlates directly with advancing age, likely due to deficient signals or signal transduction responsible for iNOS mRNA and protein generation.