Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts.

Cytokines produced by inflammatory or resident mesenchymal cells play important modulatory roles in the pathogenesis of inflammation induced bone loss. In the present study, the effects of IL-4 and IL-13 on the expression of three osteotropic cytokines in the IL-6 family expressed in human gingival fibroblasts were studied. IL-4Rα and IL-13Rα1 mRNA were constitutively expressed in human gingival fibroblasts. The inflammatory cytokines IL-1ß and TNF-α increased expression of IL-6, LIF, and IL-11 mRNA and protein in the gingival fibroblasts. Addition of IL-4 or IL-13 had no effect on IL-6 expression, but significantly inhibited LIF and IL-11 mRNA and protein stimulated by IL-1ß and TNF-α. No involvement of NF-κB or STAT1 was observed in the inhibition. STAT6 was phosphorylated at Y641 by treatment with IL-4 and knockdown of STAT6 with siRNA decreased the inhibition of IL-11 and LIF expression by IL-4 in IL-1ß and TNF-α stimulated cells. This study suggests that activation of STAT6 by IL-4 and IL-13, through type 2 IL-4 receptors, inhibits production of IL-11 and LIF stimulated by IL-1ß and TNF-α in human gingival fibroblasts. A negative modulatory role of IL-4 and IL-13 in osteotropic cytokine production could be a mechanism playing an important inhibitory role in inflammation induced periodontitis.

Periodontal disease in patients from the original Kostmann family with severe congenital neutropenia.

BACKGROUND: Patients with Kostmann syndrome (severe congenital neutropenia [SCN]) typically normalize their absolute neutrophil count (ANC) upon granulocyte colony-stimulating factor (G-CSF) therapy. However, although they no longer experience life-threatening bacterial infections, they frequently still have recurrent gingivitis and even severe periodontitis, often starting in early childhood. METHODS: We studied the periodontal disease in the four surviving patients belonging to the family originally described by Kostmann. Their odontological records, x-rays, color photos, bacterial cultures, serum antibodies to oral bacteria, and histopathological examinations were reviewed. The data were also correlated to previous investigations on their antibacterial peptides and molecular biology. RESULTS: Three patients had periodontal disease, despite normal ANC and professional dental care, and had neutrophils deficient in antibacterial peptides. One of these patients also had a heterozygous mutation in the neutrophil elastase gene, had severe periodontal disease and overgrowth of the periodontal pathogen Actinobacillus actinomycetemcomitans in the dental flora, and 15 permanent teeth had been extracted by the age of 27. One bone marrow-transplanted patient had no periodontal disease. CONCLUSIONS: Normalized ANC levels are not sufficient to maintain normal oral health in SCN patients, and because neutrophils are important for first-line defense and innate immunity, the deficiency of the antibacterial peptide LL-37 probably explains their chronic periodontal disease. Professional dental care is still important for SCN patients, despite treatment with G-CSF and normal ANC levels. Whether antibacterial peptides play a role in the pathogenesis of periodontitis in other patients remains to be elucidated.

Bone resorbing activity and cytokine levels in gingival crevicular fluid before and after treatment of periodontal disease.

BACKGROUND: The aim of the present study was to investigate bone resorption activity (BRA), interleukin-1 alpha (IL-1 alpha), IL-1 beta and interleukin-1 receptor antagonist (IL-1ra) in gingival crevicular fluid (GCF) in sites with no signs of periodontal disease and in sites with horizontal or angular loss of periodontal bone. These assessments were performed before and after periodontal treatment. METHODS: GCFs were collected from 10 individuals with filter strips from two healthy sites and four sites with deep pathological periodontal pockets, two of which showed horizontal bone loss and two with angular bone loss. All diseased pockets were treated with flap surgery and systemic Doxyferm. Twelve months later GCF was collected again and treatment outcome evaluated. BRA in GCFs was assessed in a bone organ culture system by following the release of (45)Ca from neonatal mouse calvariae. The amounts of IL-1 alpha, IL-1 beta and IL-1ra in GCFs were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment resulted in reduction of pocket depths with 3.5+/-0.5 mm in sites with angular bone loss and 2.8+/-0.3 mm in sites with horizontal bone loss. Initially, BRA, IL-1 alpha, IL-1 beta and IL-1ra were significantly higher in GCFs from diseased sites compared with healthy sites. No differences in BRA and cytokine levels were seen between GCFs from pockets with horizontal and angular bone losses. The levels of IL-1 alpha, IL-1 beta and IL-1ra were significantly reduced after treatment of diseased pockets. Pocket depths were significantly correlated to BRA only in pre-treatment sites with angular bone loss. BRA was correlated to Il-1 alpha, IL-1 beta, but not to IL-1ra, in diseased sites with angular bone loss, before and after treatment. The reductions of BRA in the individual sites, seen after treatment, were not correlated to the reductions of Il-1 alpha, IL-1 beta or IL-1ra. CONCLUSIONS: These data show that BRA and cytokine levels are increased in GCFs from sites with periodontal disease and that periodontal treatment results in reduction of the cytokines. Our findings further indicate that IL-1 alpha and IL-1 beta play important roles for the BRA present in GCFs, but that other factors also contribute to this activity.