PubMed · 3611016
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D J Das Gupta. 1987. Glomerular changes in hypoxic conditions.. https://pubmed.ncbi.nlm.nih.gov/3611016/
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Tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) antigenic sites were shown within the resident glomerular mesangial cells of lupus nephritis patients applying the colloidal gold immunocytochemical approach at the electron microscopic level. Using specific polyclonal antibodies against human recombinant (hr) TNF alpha and hrIL-6 in conjunction with the protein A-gold complex, TNF alpha and IL-6 were shown in the mesangial cells, being particularly associated with the membranes of the rough endoplasmic reticulum. In addition, IL-6 also was present in glomerular immune deposits and occasionally in glomerular epithelial cells. In normal renal tissue the TNF alpha and IL-6 immunoreactivities were undetectable. The specific presence of TNF alpha and IL-6 in pathological specimens was shown by several control experiments. Thus, our results offered morphological support that TNF alpha and IL-6 might play a role in human lupus nephritis. The data showed their synthesis by the mesangial cells and their possible participation in the progression to chronicity of the renal injury on secretion.
Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetic acid (PMA) stimulates DNA synthesis in human glomerular mesangial cells. Incubation of these cells with PMA stimulates the tyrosine phosphorylation of a set of proteins ranging from 110 to 39 kDa with different time kinetics. PMA inhibits total protein tyrosine phosphatase (PTPase) activity in these cells. Immunoprecipitation of PTP1B, an intracytoplasmic tyrosine phosphatase, with subsequent assay of the immunobeads for PTPase shows a significant inhibition of its activity in PMA-treated cells. Immunoblot analysis of mesangial cell lysates using the same antibody revealed that PMA does not affect the level of this 50 kDa PTP1B protein. These data indicate that inhibition of total PTPase, and specifically PTP1B, activity may provide a mechanism for stimulation of tyrosine phosphorylation by PMA in these cells and thereby contribute to its mitogenic effect.
Circumstantial evidence that pIgA has a key role in glomerular injury of IgAN is now strong. Although the answers to the questions posed in this review are necessarily incomplete, they do indicate that (1) pIgA is a major component of mesangial IgA. (2) circulating pIgA is increased and this pIgA is particularly enhanced during acute hematuric relapses of IgAN. As well as true J-chain-positive pIgA, other macromolecular IgA species may circulate, including CIC, rheumatoid factors and complexes with fibronectin. (3) pIgA appears not to be derived from the mucosal lamina propria and may originate in the marrow and/or tonsil which may be unduly stimulated as a result of impaired oral tolerance. (4) Abnormalities of IgA production control are several, including genetic and cellular influences. Little is yet known about abnormalities specific for pIgA, although antigen-driven pIgA responses appear exaggerated and prolonged. In addition, pIgA enhancement may be due to activation of polyclonal antigen-independent antibody production of low affinity. (5) There is some evidence that pIgA has an enhanced capacity to bind to mesangial cells and induce injury compared to mIgA. (6) As yet, it is unclear whether pIgA has particular effects on mesangial cell activity and the induction of progressive injury. While steady progress continues in the understanding of the role of pIgA in the immunopathogenesis of IgAN, the design of therapeutic strategies based on such understanding still remains a considerable way off.