No abstract

Subepithelial fibrosis in the bronchi of asthmatics is the result of an irreversible lung fibroblast activation, triggered by cytokines secreted by IL-4- and IL-5-activated inflammatory cells. Here, we provide evidence that human lung fibroblasts (ICIG7 cells) express a single class of high-affinity IL-4 receptor (IL-4R). This receptor is functional and composed of at least the IL-4Ralpha and IL-13Ralpha1 chains in the absence of the IL-2Rgamma chain. The IL-4Ralpha is efficiently internalized at 37 degrees C within 15 min in the presence of IL-4, whereas this process is slower with IL-13. In ICIG7 cells, IL-4 triggers the tyrosine phosphorylation of at least two proteins (110 and 180 kDa), and up-regulates the transcription of c-fos, c-jun and c-myc proto-oncogenes. In addition, the secretion of several cytokines [IL-6, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor (GM-CSF)] as well as the expression of beta1 integrin and VCAM-1 adhesion molecules are augmented by IL-4. IL-13 displays similar biological activities, but less effectively than IL-4. On the other hand, ICIG7 cells could constitute a lung fibroblast population defined by the spontaneous release of several pro-inflammatory cytokines (IL-6, IL-11 and GM-CSF) and cell surface phenotype (CD4 and Thy-1). Through this peculiar cytokine pattern and the IL-4/IL-13-dependent activities, these cells could act as effector cells in the pathogenesis of asthma, triggering and maintaining the recruitment, homing and activation of bone marrow-derived inflammatory cells, and playing a role in the remodeling process of the airways.

Chemokines are cytokines specialized for recruiting leukocytes in inflammatory responses. Recent data indicate that besides macrophages and leukocytes fibroblasts may also be a source of these important immune molecules. We assayed chemokine expression (mRNA /  protein) in cultured fibroblasts isolated from a variety of human tissues and different pathologic states: normal bone marrow vs. myelometaplastic spleen, normal lung vs. metastasis stroma, and normal breast vs. radiation fibrosis and tumor stroma. In all fibroblasts, transcripts for chemokines IL‐8, stromal cell‐derived factor‐1, monocyte chemotactic protein (MCP)‐1 and eotaxin were detected. Although the production of IL‐8 was abundant in most of the fibroblasts studied, fibroblasts from lung and pathologic breast tissue produced significantly less. Conversely, eotaxin production was low in most fibroblasts except in those isolated from myelometaplastic tissue where it was highly produced. Moreover, chemokines MCP‐4, RANTES and macrophage inflammatory protein‐1α were found to be expressed only in fibroblasts from select tissues. When the expression of CD40, an activating surface molecule for immune cells, was investigated, we found that most of the fibroblasts expressed this antigen. Overall these results indicate that cultured human fibroblasts from various tissues and pathologic settings produce a distinct panel of chemokines and express CD 40, suggesting a possible fundamental role of fibroblasts in immune responses and disaese processes.

Fibroblasts demonstrate different phenotypes and functions according to the tissue of origin and its physiopathologic state. We previously showed that fibroblasts isolated in culture from myelometaplasic (MM) spleen differed phenotypically from fibroblasts from normal bone marrow (BM ؉ cells was better in the presence of BM rather than MM spleen-derived fibroblasts. In addition, fibroblasts from MM spleen also induced a differentiation of CD56 ؉ natural killer (NK) cells whereas BM-derived fibroblasts did not. Overall, the data indicate that cultured fibroblasts from diseased tissue have distinct growth and differentiation regulatory characteristics. They also suggest a role for these cells in hematopoietic disorders.