Cytokine dysregulation in pulmonary sarcoidosis: insights into defense strategies of the lung

IL12 is a powerful regulator of cellular immune responses. The biologically active cytokine is a heterodimer (p70) composed of covalently linked products, p35 and p40, of two separate genes. The subunits are differentially regulated, with p35 being constitutively expressed by many cell types and p40 being inducible and tightly regulated in cells producing the functional heterodimer. Bacteria and bacterial products such as LPS, certain viruses and viral products, and protozoa are among the most powerful inducers of IL12. In peripheral blood, monocytic phagocytes and dendritic cells are the major producers of IL12. IL12 is critical to the development of Th1 immune responses by regulating the differentiation of T-cell precursors into Th1 cells, largely by stimulating IFNγ production. Thus, IL12 serves as a critical link between innate and adaptive immune host responses to many infectious agents. IL12 can be either pathogenic or beneficial depending on whether type 1 (Th1) or type 2 (Th2) immune processes are pathogenic. IL12 has been found to have a critical role in resistance to infection with intracellular parasites such as Mycobacterium tuberculosis, Leishmania major, Toxoplasma gondii and Listeria monocytogenes. In HIV-infected individuals, a relative deficiency of IL12 may contribute to a susceptibility to opportunistic infections. In contrast, IL12 can play a pathogenic role in experimental models of Th1-mediated autoimmune processes. Recently we provided evidence that pulmonary sarcoidosis is characterized by a marked polarization towards a type 1 immune process which is associated with a striking upregulation of IL12 (J. Immunol. 1996; 156: 4952). Dominant type 1 cytokine expression with elevated levels of IFNγ but not IL4 was seen at the level of both mRNA and protein in sarcoid lung cells and fluid compared with normal samples. Using semi-quantitative PCR, we found significantly higher mRNA expression of the regulated IL12 p40 subunit, but not IL10, in sarcoid compared with normal lung cells. Consistent with these observations, strikingly elevated levels of p40 protein were found in sarcoid compared with normal bronchoalveolar lavage fluid. Unstimulated and Staph. aureus-stimulated sarcoid alveolar macrophages produced greater amounts of IL12 than normal alveolar macrophages when cultured in vitro. These observations lead us to hypothesize that sarcoidosis is a Th1 mediated disease driven by chronic, dysregulated production of IL12 at sites of disease. If this hypothesis is correct, the pharmacologic control of IL12 production may be a key strategy in modulating the granulomatous inflammation in pulmonary sarcoidosis. Pentoxifylline is a methylxanthine derivative and non-selective phosphodiesterase inhibitor with anti-TNFα and anti-HIV effects. Reports of bacterial pneumonias in patients with AIDS-related wasting disease who were treated with pentoxifylline suggest this drug may increase susceptibility to some bacterial infections in this disorder, a finding incompletely explained by anti-TNFα effects. We found that pentoxifylline markedly inhibits production of IL12 by peripheral blood mononuclear cells stimulated with Staphylococcus aureus or LPS. In these same cultures, TNFα production was inhibited and IL10 production was enhanced by treatment with pentoxifylline. Using RNase protection, pentoxifylline strikingly inhibited both p40 and p35 mRNA accumulation by S. aureus-stimulated PBMC suggesting that IL12 inhibiton is transcriptionally regulated. Experiments with neutralizing anti-IL10, anti-TGFβ and the phosphodiesterase inhibitor IBMX indicate that inhibition of IL12 is mediated by elevated cAMP levels and not alterations in IL10 or TGFβ production. We conclude that pentoxifylline is a potent inhibitor of IL12 production which must be used with caution in patients with immunodeficiency. The suppressive effects of pentoxifylline on IL12 production, however, provides a firm rationale for investigating the use of this drug in Th1-mediated disorders such as sarcoidosis.