BackgroundMacrophages and fibroblasts are two major players in tissue repair and fibrosis. Despite the relevance of macrophages and fibroblasts in tissue homeostasis, remarkably little is known whether macrophages are able to influence the properties of fibroblasts. Here we investigated the role of paracrine factors secreted by classically activated (M1) and alternatively activated (M2) human macrophages on human dermal fibroblasts (HDFs).ResultsHDFs stimulated with paracrine factors from M1 macrophages showed a 10 to > 100-fold increase in the expression of the inflammatory cytokines IL6, CCL2 and CCL7 and the matrix metalloproteinases MMP1 and MMP3. This indicates that factors produced by M1 macrophages induce a fibroblast phenotype with pro-inflammatory and extracellular matrix (ECM) degrading properties. HDFs stimulated with paracrine factors secreted by M2 macrophages displayed an increased proliferation rate. Interestingly, the M1-activated pro-inflammatory fibroblasts downregulated, after exposure to paracrine factors produced by M2 macrophages or non-conditioned media, the inflammatory markers as well as MMPs and upregulated their collagen production.ConclusionsParacrine factors of M1 or M2 polarized macrophages induced different phenotypes of HDFs and the HDF phenotypes can in turn be reversed, pointing to a high dynamic plasticity of fibroblasts in the different phases of tissue repair.

These results suggest a gender difference in the balance between the specific and non-specific immune response, i.e. a more profound and higher state of excitation of the non-specific immune response and relative suppression of the cellular immune response of the specific immune system in men as compared with women.

Infection with oncogenic types of human papillomavirus (HPV) is the main causal factor of cervical cancer and its precursor lesion (cervical intraepithelial neoplasia [CIN]). Cellular immunity may be critical in the elimination of HPV-harboring cells. Interleukin-10, a T-helper type 2 cytokine, has a suppressive effect on cell-mediated immunity. Resistance to apoptosis through the Fas pathway might enable many cancers to escape the immune system. We examined in a large study population whether three polymorphisms in the IL-10 gene and a polymorphism at position -670 of the Fas promotor affect susceptibility for cervical cancer or its precursor. In addition, it was studied whether these polymorphisms were causal and not merely associated by typing microsatellite markers in the region surrounding both genes. A total of 311 CIN, 695 cervical cancer patients, and 115 family-based and 586 unrelated controls were analyzed. Association analysis revealed an increased CIN (II-III) (OR 1.44 [1.06-1.97]) and squamous cell carcinoma of the cervix (OR 1.35 [1.04-1.75]) for individuals heterozygous for the A-allele of the IL-10-592 polymorphism. In contrast to previous findings, no association was found for the IL-10-1082 polymorphism. While an increased risk for adenocarcinoma (AC) in heterozygotes (OR 1.59 [1.02-2.48]) was observed. Our study shows a possible role for the IL-10 gene in CIN and squamous cell cervical cancer susceptibility in the Caucasian population; simultaneously, there might be a role for the Fas gene in the development of AC of the cervix. Further investigations with a higher density of markers are necessary to find the causal mutation.

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