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We read with interest the report by Drynda et al demonstrating that treatment of rheumatoid arthritis (RA) with anti-tumour necrosis factor α (anti-TNFα) induces subtle changes in the cytokine network such as down regulation of the proinflammatory cytokine interleukin 6 (IL6), but does not affect the persistently high plasma levels of transforming growth factor β (TGFβ).1 Furthermore, they suggest that the latter finding indicates the existence of as yet unknown mechanisms for TGFβ overexpression in RA that may predispose a patient to severe infections and altered tumour defence.
Complementary to the observations noted above are our findings using DNA microarray in patients with RA treated with TNF antagonists as compared with patients with RA treated with methotrexate and healthy controls.2 A total of 12 000 genes were analysed (human genome U 95 A Array-Affimetrix) and a variety of gene functions, including apoptosis, transcription factors, cell survival, antigen presentation, cartilage degradation, B and T cell function, intracellular signals, transcription genes, adhesion molecules, inflammatory mediators, clotting factors, HLA class II molecules, oncogenes, cytokine production, and cytokine receptor expression, were altered (up or down regulated) in the group receiving TNF antagonists. Of interest, several proinflammatory cytokine receptors including interferon γ, TNF, IL10, and TGFβ were found to be down regulated. Therefore, pathway signalling of these cytokines including TGFβ may be impaired if their receptors are down regulated.
Altered expression of these genes' function, alone or in combination, may have an impact on the predisposition to infection and tumour defence. Such is the case for the induced TNFα inhibitor down regulation in the expression of C9, B and T cell functions, signalling cascade (↓ Jun B), adhesion molecules, heat shock proteins, and antigen presentation, and the predisposition to infection. Likewise, TNF antagonists also regulate the expression of oncogenes, such as Jun B, c-myc, fos and ras, which may have an impact on tumour defence.
Therefore, our study with DNA microarray confirms and expands the immunomodulatory functions of TNF antagonists. Data, however, seem to suggest that the increased predisposition to develop infection and altered tumour defence may not be related to increased plasma levels of TGFβ because its receptors are down regulated, but rather to dysregulation of gene expression of other molecules induced by, the TNF antagonists.2,3
We read with interest the letter by Cuchacovich and Espinoza commenting on our previous paper,1 which, based on results of DNA microarrays showing that increased plasma levels of transforming growth factor β (TGFβ) persist in the course of anti-tumour necrosis factor α (anti-TNFα) treatment in rheumatoid arthritis (RA), suggests that patients may not have an altered tumour defence.
Complex effects of TGFβ on tumour development and progression, as well as cancer metastasis have been demonstrated in numerous studies.2,3 As a result of these studies, raised levels of TGFβ seen in patients with RA are thought to contribute to an altered tumour defence.
In our own additional experiments we monitored changes in the expression profiles of mononuclear cells from peripheral blood in the course of anti-TNF treatment in RA in 10 patients using the same human genome U95a Affymetrix chip. By applying a different experimental setting than Cuchacovich et al,4 different results were found. Only a small number of genes were found to be regulated in five or more of the 10 patients in either direction after anti-TNF treatment compared with baseline. Among these genes were proinflammatory cytokines, chemokines, apoptosis related proteins, and proteins involved in the cell cycle. Interestingly, different regulation patterns were found in our patients.5 In contrast to Cuchacovich et al,4 no down regulation was found in receptors for interferon γ, interleukin 10, or in either TGFβ receptors (TGFβRI and TGFβRII) within the first six days of anti-TNF treatment. Expression of oncogenes Jun B, c-myc, ras, and fos remained unchanged as well.
Finally, it should be mentioned that neither mRNA levels nor plasma concentrations of TGFβ completely reflect the real situation in vivo because the biological activity of TGFβ is tightly regulated post-transcriptionally. This includes the proteolytic cleavage of active TGFβ from its precursor protein,6 the formation of the active ligand-receptor complex, and the downstream signalling via Smads.7
Further research is mandatory to explain the multiple effects of TGFβ and its role in the complex network of cytokines. Recently developed techniques such as DNA microarrays may help to understand the interactions and regulation of proteins and their biological activity.
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