Oligo-2,5-Adenylate Synthetase in Pulmonary Sarcoidosis and Idiopathic Pulmonary Fibrosis: Discussion

In PBML of patients with SAR and IPF, the correlations between the levels of 2,5AS activity and the ratios of monocytes to lymphocytes were analyzed. In PBML of patients with IPF and SAR, there were no significant correlations between them (data not shown). No significant correlation between the levels of BALF cell 2,5AS activity and the ratios of lung lymphocytes to PAM was found in patients with SAR, and the levels of BALF cell 2,5AS activity were not correlated to the ratios of lung PMN to PAM in patients with IPF (data not shown).
The levels of 2,5AS activity of isolated cells were measured in some cases (Table 2). In both PBML and BALF cells, the levels of 2,5AS activity from whole cells, lymphocytes, and monocytes (or PAM) exhibited almost the same levels in each case.
Correlation of the Levels of 2,5AS Activity to Clinical Parameters
We also analyzed the correlations of the levels of PBML and BALF cell 2,5AS activity to clinical markers such as ACE, lactate dehydrogenase (LDH), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). In patients with SAR, there were no significant correlations of the levels of PBML and BALF cell 2,5AS activity to the levels of serum ACE activity (data not shown). To LDH, CRP, or ESR, significant correlations of the levels of PBML and BALF cell 2,5AS activity were found in patients with IPF (data not shown).

Interferons are a family of secreted polypeptides with distinctive biologic effects that include regulation of specific genes, inhibition of cell growth and proliferation, and modulation of cell differentiation. Interferons consist of three antigenically distinct subclasses: alpha, beta, and gamma. The interaction of these IFNs with specific high-affinity receptors in the cell membrane results in the induction of a number of genes. One of these genes that encodes 2,5AS, has been characterized in detail, and the transcriptional activation by IFNs has been shown to parallel closely IFN receptor interaction. Although there are at least two distinct IFN receptors (type 1 to IFN-alpha/beta and type 2 to IFN-gamma), IFNs can induce 2,5AS through functionally distinct receptors. The 2,5AS is the enzyme to convert ATP into 2,5A with 2′,5′ linkage, and the enzyme product 2,5A activates a latent endoribo-nuclease that degrades mRNA. The 2,5A is rapidly degraded, so the activation of the nuclease and inhibition of protein synthesis is transient. Thus, the 2,5A system can provide a possible mechanism for limiting the proliferative response of cells to mitogens. Hence, the measurement of this enzyme activity is able to evaluate the exposure of IFNs to cells. Moreover, the enzyme assay is more sensitive than assays of IFN in the serum: in human cultures we routinely observe that 5 to 10 U IFN per milliliter produces a twofold to fivefold increase in the enzyme level, as found by Minks et al. Levels of circulating IFN do not necessarily reflect the state of the IFN system in a patient, because circulating IFNs have a very short half-life.

Table 2 — Oligo-2′,5′ -Adenylate Synthetase Activity in Isolated CeUs of Peropheral Blood and BALF

No.ofCases Peripheral Blood i BALFi
rWhole Lymph Mono rWhole PAM Lymph
NC 1 11.3 14.4 12.1 65.1 57.6 71.4
2 15.3 10.1 15.0 105.6 112.7 98.2
3 8.0 7.1 7.6 44.1 39.4 38.7
SAR 1 67.5 72.6 68.4 107.5 104.5 98.1
2 31.8 27.8 35.7 251.5 218.6 261.3
IPF 1 134.3 108.9 121.7 43.3 34.3 40.7
2 237.2 252.9 218.9 132.9 151.2 118.4
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