Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease

Abstract

Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection.

Fig. 1

Box plots (10th, 25th, 50th, 75th and 90th percentiles) showing cytokine expression levels (mean mRNA/0·5 µg total RNA) during latent tuberculosis (LTB) in the lungs of infected mice. The expression levels of interleukin (IL)-15, interferon (IFN)-γ and IL-12 showed a decreasing trend from phases 1 to 3. However, IL-10 levels showed an increasing trend. IL-2 and tumour necrosis factor (TNF)-α levels showed an increasing trend from phases 1 to 2 but a decreasing trend from 2 to 3. However, none of the differences was significant. IL-4 expression levels increased significantly (P = 0·02) from phases 1 to 2 but decreased significantly (P = 0·02) from phases 2 to 3 in the lungs of infected mice.

Fig. 2

Box plots showing cytokine expression levels (mean mRNA/0·5 µg total RNA) in the lungs of infected mice during slowly progressive primary tuberculosis (SPTB). The expression levels of interleukin (IL)-15 increased significantly (P < 0·0001) from phases 1 to 2 and from 2 to 3 (P = 0·01). The expression levels of interferon (IFN)-γ, IL-12 and IL-10 increased significantly from phases 2 to 3 (P = 0·003, P = 0·006 and P = 0·007, respectively). However, no significant changes were observed in the expression levels of IL-2, IL-4 and tumour necrosis factor (TNF)-α in the lungs of infected mice.

Fig. 3

Box plots showing cytokine expression levels (mean RNA/0·5 µg total RNA) in the spleens of mice during latent tuberculosis (LTB). Similar to the lungs, cytokine expression was depressed during LTB in the spleens. Levels of interleukin (IL)-15 showed a decreasing trend from phases 1 to 3 but the differences were not statistically significant. Interferon (IFN)-γ levels decreased significantly (P = 0·01, P = 0·02) from phases 1 to 2. Levels of IL-10 increased significantly (P = 0·02) from phases 2 to 3.

Fig. 4

Box plots (10th, 25th, 50th, 75th and 90th percentiles) showing cytokine expression levels (mean mRNA/0·5 µg total RNA) in the spleens of mice during slowly progressive primary tuberculosis (SPTB). The expression levels of interleukin (IL)-15 increased significantly (P = 0·03) from phases 2 to 3. IL-12 decreased significantly (P = 0·03) from phases 1 to 2 but increased again from phases 2 to 3 (P = 0·02). IL-10 increased significantly (P = 0·005) from phases 2 to 3. IL-2 decreased significantly (P = 0·049) from phases 1 to 2. Tumour necrosis factor (TNF)-α decreased significantly (P = 0·001) from phases 2 to 3.