Tuberculosis is an infectious disease with a long history. Despite the development of effective anti-tuberculosis drugs, its prevalence has been increasing associated with appearances of acquired immunodeficiency syndrome and drug-resistant tuberculosis, which make it difficult to manage and prevent tuberculosis. Understanding the pathogenesis of tuberculosis will help advance therapy from one currently based on anti-tuberculosis drugs to one using immune regulation.

Cell-mediated immune response to Mycobacterium tuberculosis is primarily mediated by macrophages and T-lymphocytes^{1, 2)}. M. tuberculosis can invade and multiply in tissue macrophages as well as in alveolar macrophages²⁾. Macrophages ingesting M. tuberculosis produce a characteristic pattern of cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, transforming growth factor (TGF)-β, monocyte chemoattractant protein (MCP)-1, and regulated on activation, normal T-cell expressed and secreted (RANTES)^2–4). In addition, they process and present mycobacterial antigens to T-lymphocytes, which in turn produce additional cytokines. These cytokines produced by macrophages and T-lymphocytes reactivate macrophages, which remove M. tuberculosis more effectively. On the other hand, cytotoxic T-lymphocytes lyse macrophages and the other cells infected with M. tuberculosis. Cytotoxic T-cells can directly inhibit mycobacterial growth⁵⁾ and release bacilli that can be ingested and killed by macrophages with greater anti-mycobacterial activity⁶⁾.

In this study, to evaluate the changes in plasma IL-1 receptor antagonist, the cytokine levels of an endogenous inhibitor of IL-1, a pivotal proinflammatory cytokine, and IL-8, a chemokine for leukocytes recruitment and granuloma formation, they were compared with other inflammatory markers as patients with active pulmonary tuberculosis received treatment.

The mean age of the 18 subjects (11 males and 7 females) was 43.6±21.9 years. On diagnosis, the mean BMI was 19.5±2.4 kg/m². There were 3 retreatment cases and 3 diabetic patients. Twelve patients had positive sputum AFB smears; one had negative smear but positive AFB culture, and one showed positive AFB in bronchial washing. Among 12 patients receiving drug-sensitivity tests, we found two drug resistant cases. Five patients had endobronchial tuberculosis, and two patients with confirmative biopsy were complicated with TB lymphadenitis and intestinal TB, respectively (Table 2). Thirteen patients belonged to the early-response group, and 5 patients belonged to the delayed-response group according to the criteria in Table 1.

Hemoglobin, hematocrit, WBCs, platelets, ESR, CRP, ferritin, and plasma IL-1ra changed significantly during the treatment period. After 2 months of treatment, ESR and CRP were significantly diminished. After 6 months of treatment, hemoglobin increased and WBCs, platelets, ESR, and ferritin decreased significantly from pre-treatment levels (Table 3).

At each measurement, the delayed-response patients showed lower body weight, hemoglobin and hematocrit, and higher WBCs, platelets, ESR, IL-8 and IL-1ra than the early-response patients. During the course of the treatment, there were significant differences in body weight, body mass index, hemoglobin, hematocrit, WBCs, platelets, ESR, CRP and ferritin within both groups (Table 4, Figure 1–6).

Cytokines have multiple functions as intercellular signaling substances through intracellular signal transduction and the second messenger pathway^{10, 11)}. So far, among many known cytokines, IL-1 and TNF-α are the earliest cytokines secreted by infection and play a central role in orchestrating an inflammatory response. When infected by M. tuberculosis, not only do alveolar macrophages recruit T-lymphocytes and secret IL-1 for antigen presentation, but they also inhibit the effect of IL-1 by producing IL-1ra¹²⁾. While plasma IL-1 and TNF-α were not easily detectable, IL-1ra serum concentrations increased in patients with severe symptoms, such as fever, and correlated with clinical courses¹³⁾. Since IL-1ra acts by binding to a IL-1 receptor and alveolar macrophages are known to normally produce IL-1ra after their elaboration of IL-1, we assumed IL-1ra to be an integral, self-limiting measure. Under stimulation from IL-4, which are produced by Th2 CD4 cells, there was early and enhanced production of IL-1ra and reduced production of IL-1, potentially a mechanism to preserve the lung from excessive inflammation¹⁴⁾. In previous studies, the plasma IL-1ra level increased at the early stage of sepsis^15–17). Moreover, in experimental models, injection of endotoxin increased plasma IL-1ra^{16, 17)}. Tsao et al. noted an imbalance between cytokines and their endogenous receptors or antagonists by demonstrating increased ratios of TNF-α to soluble TNF-α receptors and IL-1 to IL-1ra in bronchoalveolar lavage (BAL) fluids of patients with cavitary pulmonary tuberculosis¹⁸⁾.

In this study, to evaluate the dynamics of plasma IL-1ra and IL-8 levels, we compared these with other hematologic and serologic parameters. During treatment, body weight, BMI, hemoglobin, and hematocrit improved and WBCs platelets, ESR, CRP, and ferritin diminished. Since these findings were consistent with previous studies^19–21), these parameters served as a good standard for evaluating IL-1ra and IL-8. The plasma IL-1ra level was highest before treatment and this indirectly reflects increased production of IL-1. In particular the concentration of IL-1ra declined rapidly in the early-response group after treatment. Similar to ESR and CRP, IL-1ra could be useful as a marker reflecting disease activity and treatment response in patients with tuberculosis.

IL-8 is a chemokine that attracts lymphocytes as well as polymorphonuclear neutrophils. M. tuberculosis, ingested by human monocytes, is a strong stimulus for gene expression and secretion of IL-8 and chemotaxis of antigen-specific T-lymphocytes^22–24). IL-8 plays a role in leukocytes recruitment and granuloma formation²⁵⁾. Following phagocytosis of M. tuberculosis, human polymorphonuclear neutrophils secrete IL-8 to attract inflammatory cells to the inflammation site^{26, 27)}. Considering the role of IL-8, its local concentration was expected to be much higher than its systemic concentration and IL-8 concentration of BAL, pleural fluid, and cerebrospinal fluid in tuberculous patients were appreciated^28–30), whereas some reports showed blood level of IL-8 was relatively higher than the other chemokines were^{28, 31)} and high plasma IL-8 level was observed in patients dying of tuberculosis³²⁾. In addition, others observed high plasma concentration of IL-8 in patients with severe sepsis and Plasmodium falciparum infections^{33, 34)}.

Since early inflammatory cytokines act on effecter cells, which Secrete IL-8, we assumed the peak point of IL-8 secretion to be different from that of IL-1ra. We observed higher plasma IL-8 levels after 2 months of treatment than those before treatment. Furthermore, delayed-response patients exhibited higher plasma IL-8 concentrations than early response patients at all three intervals. In particular, the IL-8 level after 6 months was higher than pre-treatment level in the delayed-response group. IL-8 seemed to be an indicator for delayed inflammatory response. In order to confirm this, an investigation using a longer follow-up period and a larger pool is needed. Moreover, plasma IL-8 measurements may not be enough to elucidate the role of IL-8 related to local infection or inflammation³⁵⁾, and considering IL-8 activity in tissue, its plasma concentration should be different from the tissue’s concentration.

In this study, IL-1ra and IL-8 did not seem to be as sensitive as other serologic markers to reflect diminished inflammatory responses related to treatment. While other markers were easily measured, measurements of IL-1ra and IL-8 by ELISA showed low reproducibility, and their clinical application may be limited. IL-1ra is an endogenous inhibitor of IL-1, which is a proinflammatory cytokine that induces fever, weight loss, and hypotension with TNF-α, and indirectly reflects the degree of IL-1 production. In patients with active pulmonary tuberculosis, IL-1ra could be a marker to evaluate disease activity and treatment response. A study including a long follow-up period is required to better evaluate the significance of IL-8 as an indicator of delayed response.